Systems for gel-based medical implants

ABSTRACT

Systems, including methods and apparatus, for medical implants including a gel.

CROSS-REFERENCES TO PRIORITY APPLICATIONS

This application is based upon and claims the benefit under 35 U.S.C.§119(e) of the following U.S. provisional patent applications: Ser. No.60/529,470, filed Dec. 15, 2003; Ser. No. 60/529,479, filed Dec. 15,2003; Ser. No. 60/529,489, filed Dec. 15, 2003; and Ser. No. 60/529,534,filed Dec. 15, 2003. Each of these applications is incorporated hereinby reference in its entirety for all purposes.

BACKGROUND

The human body has numerous vessels and organs that transport bodilyfluids for nutrient delivery, recirculation and excretion of byproducts.Many of these structures have a tubular geometry, for example, bloodvessels, the intestinal tract, and the bladder. Even relatively solidorgans such as the heart, liver, kidney and pancreas have tubularcavities and lumens. Furthermore, disease processes such as tumors andaneurysms may create spaces or voids within otherwise solid organs.

The lumens afforded by organs and vessels can be affected by a varietyof diseases and medical conditions. For example, a lumen may beoccluded, thus limiting or blocking flow through the lumen. Since thelumen of many organs and vessels serve vital functions, such asproviding a conduit for blood, urine, bile, or food, restriction of flowthrough the lumen is usually undesirable. The growth of an occludingatheroma in an artery is an exemplary restriction that impedes bloodflow.

Devices, materials and methods for the treatment and repair of tissuesaround vessel or organ lumens continue to be developed to minimize oreliminate restrictions within the lumens. Many of the newer treatmentsaccess the medial, endomural zone of organs, organ components, or vesseltissues via surgical or percutaneous procedures. With many of thesetreatment procedures, inflammation, proliferative regrowth, andexcessive ingrowth of tissue may occur in response to the trauma orvascular damage near the treatment area, lessening clinicaleffectiveness.

Medical researchers of coronary disease, for example, are working todevelop better medical practices for inhibiting stenosis, the narrowingor constricting of a blood vessel lumen, and for preventing orminimizing restenosis that may occur after a procedure such asangioplasty. Atherosclerosis, which is characterized by the progressivebuildup of hard plaque in the coronary arteries, as well as other typesof stenoses are treated by a number of procedures, including balloondilatation, stenting, ablation, atherectomy or laser treatment.Stenosis, restenosis, and cancerous growth or tumors may block otherbody passageways besides coronary arteries, including the esophagus,bile ducts, trachea, intestine, and the urethra, among others.

Although angioplasty and stenting procedures are probably the best-knownprocedures for treating stenosis within vessels, other treatments areavailable. In cases of severe atherosclerotic obstructions, endovascularremoval of obstructive lesions via endovascular atherectomy, acatheter-based cutting or drilling procedure from within the vessel, maybe employed. For example, directional coronary atherectomy involves asmall sharp blade directed from inside a catheter to cut and ablateplaque from the wall of the artery. For another example, rotationalatherectomy or rotablation procedures drill through plaque with adiamond-coated burr and pulverize the buildup of cholesterol or otherfatty substances into small particles that can enter the bloodstream.While these procedures remove the diseased atheroma close to the vessellumen and treatment device, they do not address the source or core ofthe disease that often lies in the vessel media.

One common minimally invasive medical procedure for treating variouscoronary artery diseases is percutaneous transluminal coronaryangioplasty (PTCA), also called balloon angioplasty. PTCA can relievemyocardial ischemia by reducing lumen obstruction and improving coronaryflow. After a catheter is introduced into a blood vessel and advanced toa treatment site, a small dilating balloon at the distal end of thecatheter is passed across an atherosclerotic plaque and inflated tocompress the plaque and expand an occluded region of the blood vessel.This compression cracks or otherwise mechanically deforms the lesion andincreases the lumen size of the vessel, which in turn increases bloodflow. In PTCA, the blockage is not actually removed, but is compressedinto the arterial walls.

While PTCA represents therapeutic advances in the treatment of coronaryartery disease, vessel renarrowing or reclosure of the vessel oftenoccurs after PTCA, due in part to trauma of the vessel caused by theballoon dilation or stent placement. In some cases, the vessel revertseither abruptly or progressively to its occluded condition, limiting theeffectiveness of the PTCA procedure.

A medical implant such as an intravascular stent may be used to supportthe vessel, thus mechanically keeping the vessel open and preventingpost-angioplasty vessel reclosure. One common catheter proceduredelivers the stent in a compressed form to the treatment site where thestent expands via the inflation of a catheter balloon or throughself-expansion to engage the wall of the coronary or peripheral vessel.Most stents are fabricated from metals, alloys or polymers and remain inthe blood vessel indefinitely. Stent manufacturers have developed stentsof various diameters and lengths to allow anatomic flexibility, althoughthe stents may not be flexible enough to conform completely to the shapeof the vessel being treated. In some cases, a stent itself can causeundesirable local thrombosis, create restenosis due to over-expansionwithin the vessel, or result in metal ion migration from the stentlatticework.

Restenosis, the gradual narrowing of a vessel, can occur afterinterventional procedures such as stenting and angioplasty thattraumatize the vessel wall. Such trauma may lead to the formation oflocal thrombosis or blood clotting, which is most likely to occur soonafter an intravascular procedure. To address the problem of thrombosis,patients receiving stents also may receive extensive systemic treatmentwith anti-coagulants such as aspirin and anti-platelet drugs.

An uncontrolled migration and proliferation of smooth muscle cells,combined with extracellular matrix production, may develop during thefirst three to six months after a procedure when vessel trauma occurred.Scar-like proliferation of endothelial cells that normally line bloodvessels may incur restenosis, and with stent placement, there may be aningrowth of tissue proliferation or inflammatory material through theinterstices of the stent that can block and occlude the vessel.

Unfortunately, restenosis frequently necessitates further interventionssuch as repeat angioplasty or coronary bypass surgery. Alternativeprocedures, such as delivering radiation with intracoronarybrachytherapy, have been used in an effort to curtail overproduction ofcells in the traumatized area.

A significant amount of medical research continues to focus on theprevention and treatment of hard and soft plaque within vessels, onearea of study being local drug delivery to diseased or traumatizedtreatment areas. For example, in an effort to prevent restenosisprovoked by medical procedures, systems and methods have been developedto locally deliver pharmacological agents such as rapamycin, animmunosuppressant known for its anti-proliferation properties, orpaclitaxel, a chemotherapy agent and microtubular stabilizer that causescells to stop dividing due to a mitotic block between metaphase andanaphase of cell division. Some of these inhibitory pharmacologicalagents have the potential to interfere or delay healing, weakening thestructure or elasticity of the newly healed vessel wall and damagingsurrounding endothelium and/or other medial smooth muscle cells. Deadand dying cells release mitogenic agents that may stimulate additionalsmooth muscle cell proliferation and exacerbate stenosis.

While restenosis from hard-plaque obstructions can be a cause ofmyocardial infarction, known commonly as a heart attack, recent medicalresearch suggests that the development and rupture of non-occlusive,soft atherosclerotic or vulnerable plaques in coronary arteries may playa greater role in heart attacks than restenosis caused from hardplaques. Research suggests that vulnerable plaques have a denseinfiltrate of macrophages within a thin fibrous cap that overlies a poolof lipid. Vulnerable plaque is formed from droplets of lipid that areabsorbed by an artery, which can cause the release of proteins calledcytokines that exacerbate inflammation. The cytokines act as anadhesive, attracting monocytes, so-called immune-system cells, to theartery wall where they push into the tissue of the wall. The monocyteschange into macrophages, cells of the reticuloendothelial system, whichbegin to soak up fat droplets and form a plaque with a thin covering.

The rupture of vulnerable plaques, due to inflammatory processes andmechanical stress like increased blood pressure, results in exposure ofblood to the lipid core and other plaque components. Vulnerable plaqueerodes or ruptures, creating a raw tissue surface that forms scabs, andpieces of plaque that break off may accumulate in the coronary artery tocreate a thrombus of sufficient size to slow down or stop blood flow.

Vulnerable plaque is ingrained under the arterial wall and is difficultto detect with conventional means such as angiography or fluoroscopy.Thermography, which is capable of detecting a temperature differencebetween atherosclerotic plaque and healthy vessel walls, is one of theimaging methods being pursued for locating vulnerable plaque.

Unnecessary tissue damage continues to be an issue for many percutaneousprocedures and endoluminal treatments of diseased vessels. Therefore,improved systems, including methods and apparatus, for treating diseasedorgan lumens, blood vessels, and other endoluminal vessels are needed tominimize or eliminate damage to surrounding tissue, to preventrestenosis of treated areas, and/or to prevent inflammation of diseasedareas. The desirable treatment of specific tissues may providemechanical support for the lumen and sustained local delivery oftherapeutic compositions to help tissue to heal while avoiding excessivedrug levels. More specifically, improved systems for treating coronaryartery disease may minimize inflammation, restenosis, and/or theingrowth of host tissue proliferation; control the dosage and deliveryof therapeutic components to vascular tissue and smooth muscle cellsover extended periods of time; successfully treat vulnerable plaque;and/or treat or prevent undesirable medical conditions within a vessel.

SUMMARY

The present teachings provide systems, including methods and apparatus,for medical implants including a gel.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present teachings are illustrated by theaccompanying figures, with the figures not necessarily drawn to scale.

FIG. 1 is a side view of an exemplary coated stent, in accordance withaspects of the present teachings.

FIG. 2 is a sectional view of the coated stent of FIG. 1, takengenerally along line A-A′ of FIG. 1.

FIG. 3 is a partially sectional view of the coated stent of FIG. 1deployed in a vessel and releasing therapeutic agents, in accordancewith aspects of the present teachings.

FIG. 4 is a schematic diagram of an exemplary method of coating amedical implant with a gel, in accordance with aspects of the presentteachings.

FIG. 5 is a flow diagram of an exemplary method of treating a vessel ina mammalian body, in accordance with aspects of the present teachings.

FIG. 6 is a view of an exemplary system for treating a vessel in amammalian body, in accordance with aspects of the present teachings.

FIG. 7 is a longitudinal sectional view of an exemplary gel-based stent,in accordance with aspects of the present teachings.

FIG. 8 is a sectional view of the gel-based stent of FIG. 7, takengenerally along line A-A′ of FIG. 7.

FIG. 9 is a view of an exemplary gel-based stent formed to include aplurality of apertures, in accordance with aspects of the presentteachings.

FIG. 10 is a flow diagram of an exemplary method of treating a vessel ina mammalian body, in accordance with aspects of the present teachings.

FIG. 11 is a longitudinal sectional view of an exemplary alginate stentbeing formed within a vessel of a mammalian body, in accordance withaspects of the present teachings.

FIG. 12 is a longitudinal sectional view of an exemplary alginate stentformed within a vessel of a mammalian body, in accordance with aspectsof the present teachings.

FIG. 13 is a flow diagram of an exemplary method of forming an alginatestent in a vessel of a mammalian body, in accordance with aspects of thepresent teachings.

FIG. 14 is a longitudinal sectional view of an exemplary alginate stentbeing formed within a vessel of a mammalian body, in accordance withaspects of the present teachings.

FIG. 15 is a longitudinal sectional view of an exemplary alginate stentformed within a vessel of a mammalian body, in accordance with aspectsof the present teachings.

FIG. 16 is a flow diagram of another exemplary method of forming analginate stent in a vessel of a mammalian body, in accordance withaspects of the present teachings.

FIGS. 17 a-f are longitudinal sectional views of exemplaryconfigurations produced by performing an exemplary method of forming analginate stent in a mammalian body, in accordance with aspects of thepresent teachings.

FIG. 18 is a longitudinal sectional view of an exemplary alginate stentformed within a vessel of a mammalian body, in accordance with aspectsof the present teachings.

FIG. 19 is a flow diagram of yet another exemplary method of forming analginate stent in a vessel of a mammalian body, in accordance withaspects of the present teachings.

FIG. 20 is a view of an exemplary alginate bioreactor for treating amammalian body, in accordance with aspects of the present teachings.

FIG. 21 is a somewhat schematic view of an exemplary system for formingan alginate bioreactor in a mammalian body, in accordance with aspectsof the present teachings.

DETAILED DESCRIPTION

The present teachings provide systems, including methods and apparatus,for medical implants including a gel. The implants may be formed outsideof implant recipients or in situ in the recipients. The gel may be acoating disposed on the body of each implant and/or may form at least asubstantial portion of the body of each implant. The gel may includesource components configured to serve as a source of therapeutic agentsreleased from the gel. The source components may include therapeuticcomponents (chemical substances) and/or cellular components (cells). Theimplants may be used to treat and/or prevent any suitable medicalcondition, such as vulnerable plaque, stenosis, restenosis, thrombosis,saphenous vein graft disease, and/or diabetes. Other medical conditionsthat may be treated and/or prevented with the implants are disclosedelsewhere in the present teachings.

The present teachings may provide a stent including a stent latticeworkand a gel-based coating (such as an alginate gel) disposed on the stentlatticework.

The present teachings may provide a method of treating a vessel in amammalian body. The method may include steps of providing a stentlatticework and coating the stent latticework with an alginate solutionto form a coated stent having an alginate coating disposed on the stentlatticework. The coated stent may be positioned within the vessel anddeployed (for example, allowed to expand into engagement with the vesselwall from a compressed state). A therapeutic agent may be eluted fromthe alginate coating.

The present teachings may provide an alginate coating for an implantablemedical device. The alginate coating may include an alginate matrix andone or more therapeutic components and/or one or more cellularcomponents (cells) (and/or types of cellular components) dispersedwithin the alginate matrix.

The present teachings may provide a gel-based implant, such as analginate stent and/or cap (lining) for treating a vessel in a mammalianbody. The implant may provide support, release therapeutic agents,and/or the like. In some examples, the implant may be configured tocover vulnerable plaque. The implant may include an alginate matrix incontact with an endoluminal wall of the vessel and/or vulnerable plaqueand a central lumen extending axially through the alginate matrix.

The present teachings may provide a method of treating a vessel and/orvulnerable plaque in a mammalian body. A gel-based implant (such as analginate stent and/or a cap) may be formed within the vessel, and atherapeutic agent may be eluted from one or more therapeutic componentsand/or cellular components (cells) dispersed within the implant. Theimplant may be in contact with an endoluminal wall of the vessel (and/orvulnerable plaque thereof) and may have a central lumen extendingaxially through the alginate stent.

The present teachings may provide a system for forming a gel-basedimplant (such as an alginate stent and/or cap) in a mammalian body. Thesystem may include an implant formation catheter having a catheter body,a formation balloon attached to the catheter body near a distal end ofthe catheter body, and a gel-delivery lumen within the catheter body. Animplant may be formed on an endoluminal wall of the vessel (and/or onvulnerable plaque) from a fluent pre-gel solution (such as an alginatesolution) injected through the gel-delivery lumen into a cavity betweenthe formation balloon and an endoluminal wall of the vessel when theformation balloon is inflated.

The present teachings may provide a method of forming a gel-basedimplant (such as an alginate stent and/or a cap) in situ in a vessel ofa mammalian body. An implant-formation catheter having a catheter bodymay be positioned in the vessel. A formation balloon may be attached tothe catheter body near a distal end of the catheter body and may beinflated. A pre-gel solution (such as a fluent alginate solution) may beinjected through a gel-delivery lumen into a cavity formed between theinflated formation balloon and an endoluminal wall of the vessel. Thepre-gel solution may harden (gel such as by cross-linking) from a fluentto a nonfluent state to form the implant.

The present teachings may provide a system for forming a gel-basedimplant (such as an alginate stent and/or cap) in a mammalian body, forexample, to treat vulnerable plaque and/or reduce stenosis, amongothers. The system may include an implant-formation catheter having acatheter body. A distal occlusion balloon may be attached to thecatheter body near a distal end of the catheter body. A proximalocclusion balloon may be attached to the catheter body proximal to thedistal occlusion balloon. A medial formation balloon may be attached tothe catheter body between the distal occlusion balloon and the proximalocclusion balloon. A gel-delivery lumen may be included within thecatheter body. A gel-based implant may be formed from a pre-gel solution(such as a fluent alginate solution) injected through the gel-deliverylumen into a cavity between the medial formation balloon and anendoluminal wall of the vessel when the distal occlusion balloon and theproximal occlusion balloon are inflated.

The present teachings may provide a method of forming a gel-basedimplant (such as an alginate stent and/or cap, among others) in a vesselof a mammalian body. An implant-formation catheter having a catheterbody may be positioned in the vessel. A distal occlusion balloon may beattached to the catheter body near a distal end of the catheter body andmay be inflated. A proximal occlusion balloon may be attached to thecatheter body proximal to the distal balloon and may be inflated. Amedial formation balloon may be attached to the catheter body betweenthe distal occlusion balloon and the proximal occlusion balloon and maybe inflated. A pre-gel solution may be injected through a gel-deliverylumen into a cavity formed between the inflated distal occlusionballoon, the inflated proximal occlusion balloon, the inflated medialformation balloon, and an endoluminal wall of the vessel. The pre-gelsolution may be hardened (gelled) from a fluent to a nonfluent state toform the implant, for example, to cover vulnerable plaque and/or tocreate an endoluminal lining and/or support, among others.

The present teachings may provide a system for forming a gel-basedimplant (such as an alginate stent and/or cap, among others) in amammalian body. The system may include an implant-formation catheterhaving a catheter body, an angioplasty balloon attached to the catheterbody near a distal end of the catheter body, a formation balloonattached to the catheter body proximal to the angioplasty balloon, and agel-delivery lumen within the catheter body. A gelling agent, configuredto stimulate formation of a gel from a pre-gel solution, may be disposedon a surface of the angioplasty balloon. A gel-based implant may beformed from a pre-gel solution injected through the gel-delivery lumeninto a cavity between the formation balloon and an endoluminal wall ofthe vessel when the formation balloon is inflated.

The present teachings may provide a method of forming a gel-basedimplant (such as an alginate stent, cap, and/or lining, among others) ina vessel of a mammalian body, for example on vulnerable plaque and/or anendoluminal wall of the vessel. An implant-formation catheter having acatheter body may be positioned at a first location in the vessel. Anangioplasty balloon may be attached to the catheter body near a distalend of the catheter and may include a gelling (or linking) agentconfigured to stimulate formation of a gel from a pre-gel solution,disposed on a surface of the angioplasty balloon, and may be inflated.The gelling agent may be deposited on an endoluminal wall of the vessel.The angioplasty balloon may be deflated and repositioned at a secondlocation in the vessel distal to the first location. The angioplastyballoon may be re-inflated. A formation balloon may be attached to thecatheter body proximal to the angioplasty balloon and inflated. A fluentpre-gel solution may be injected through a gel-delivery lumen into acavity formed between the formation balloon and an endoluminal wall ofthe vessel. The pre-gel solution may be hardened (gelled) by the gellingagent deposited on the endoluminal wall of the vessel.

The present teachings may provide a system for forming a gel-basedimplant (such as a stent, cap, and/or lining, among others) in a vesselof a mammalian body. The system may include an implant-formationcatheter having a catheter body and a gel-delivery lumen within thecatheter body, and at least one formation balloon attached proximal to adistal end of the catheter body. A gel-based implant may be formed inthe vessel when the implant-formation catheter is inserted into thevessel and a pre-gel solution is injected through the gel-delivery lumeninto a cavity formed between the formation balloon and an endoluminalwall of the vessel.

The present teachings may provide a method of forming a gel-basedimplant in a vessel of a mammalian body. An implant-formation catheterwith at least one formation balloon may be inserted into the vessel. Apre-gel solution may be injected into a cavity formed between theformation balloon and an endoluminal wall of the vessel when theformation balloon is inflated. The pre-gel solution may be hardened(gelled) to form the implant, and the implant-formation catheter may bewithdrawn from the vessel. The implant thus formed may be in contactwith the endoluminal wall of the vessel and may include a central lumenextending axially through the implant.

The present teachings may provide a gel-based (such as alginate)bioreactor for treating a mammalian body. The bioreactor may include agel matrix and a therapeutic component and/or a cellular componentdispersed within the gel matrix. The therapeutic and/or cellularcomponent may be configured so that a therapeutic agent is released fromthe gel matrix after the bioreactor is formed within a mammalian body.

The present teachings may provide a method of treating a medicalcondition in a mammalian body. A gel-based (such as alginate) bioreactorincluding a gel matrix may be formed within a portion of the mammalianbody. The bioreactor may include a chemical substance(s) and/or cellsdispersed within the bioreactor and may be configured to serve as asource of a therapeutic agent that is released progressively from thebioreactor.

Another aspect of the invention is a system for forming an alginatebioreactor in mammalian body. The system may include a first chamber, asecond chamber, and an alginate solution injector fluidly coupled to thefirst chamber and the second chamber. An alginate solution from thefirst chamber may be injected into a portion of the mammalian body withan alginate linking and/or gelling agent from the second chamber to formthe alginate bioreactor.

I. Gels

The implants of the present teachings may include and/or may be formedat least substantially of a gel. A gel, as used herein, is anysemi-solid material formed by a solid matrix holding liquid. The gel maybe bioabsorbable (bio-erodible) or nonbioabsorbable. Exemplary gels mayinclude a matrix formed of protein, polysaccharides, syntheticcompounds, etc. In some examples, the gels may be hydrogels, that is,gels including water substantially or completely as the liquid. Thematrix of a gel may be formed partially or completely of any suitablematerial, for example, alginate, karaya gum, gelatin, albumin, collagen,polymalic acid, polyamino acids, polyacrylates, polyethylene glycols,starch, cellulose, guar gum, agar, carrageenans, pectin, polyglycolides,polylactides, polydioxanones, and/or the like. The matrix may includeone or more types of subunits that are polymerized and/or cross-linkedinto a network to form the matrix.

The gel may include a matrix formed at least substantially of alginate.An alginate matrix generally includes a three-dimensional matrix formedat least substantially of guluronate and/or mannuronate subunits, and/orderivatives thereof. Alginate may be obtained from any suitable source,for example, extracted from brown seaweeds, such as Phaeophyceae andLaminaria. In addition, the alginate may be isolated in, or processedinto, a fluent (pre-gel) form of linear chains including guluronateand/or mannuronate subunits. The chains may be cross-linked with agelling (linking) agent, to produce a substantially nonfluentthree-dimensional matrix. Each chain may include any ratio of guluronateand/or mannuronate subunits, and in any relative disposition. In someexamples, each chain may include homopolymeric blocks of mannuronatealginate subunits and/or guluronate alginate subunits, covalently linkedtogether in different sequences or blocks. In some examples, thealginate subunits can appear in homopolymeric blocks of consecutiveguluronate alginate subunits, consecutive mannuronate alginate subunits,alternating mannuronate alginate subunits and guluronate alginatesubunits, other systematic arrangements, or randomly organized blocks.The relative amount of each block type may vary with the source of thealginate. Alternating blocks of mannuronate alginate subunits andguluronate alginate subunits may form more flexible chains and may bemore soluble at lower pH than other block configurations. Blocks ofguluronate alginate subunits may form stiffer chain elements, and twoguluronate alginate subunitic blocks of more than six subunits each mayform stable cross-linked junctions with divalent cations such as Ca²⁺,Ba²⁺, Sr²⁺, and Mg²⁺, leading to a three-dimensional gel network oralginate matrix.

At low pH, protonized alginates may form acidic gels. The homopolymericblocks may form the majority of the junctions, and the relative contentof guluronate alginate subunits may determine the stability of the gel.

In some examples, alginate gels can develop and set at temperaturesclose to room temperature. This property may be useful in applicationsinvolving fragile materials like cells or tissue with low tolerance forhigher temperatures.

The alginate polymers may serve as thermally stable cold-setting gels inthe presence of divalent cations, such as calcium ions from calciumsources. Gelling can depend on ion binding, with divalent cationaddition being important for the production of homogeneous gels, forexample, by ionic diffusion or controlled acidification of calciumcarbonate. High guluronate alginate subunit content may produce strong,brittle gels with good heat stability, whereas high mannuronate alginatesubunit content may produce weaker, more elastic gels. At low or veryhigh divalent calcium concentrations, high mannuronate alginates mayproduce stronger gels. When the average chain lengths are notparticularly short, gelling properties may correlate with the averageguluronate alginate subunit block length having an optimum block size ofabout twelve subunits, and do not necessarily correlate with the ratioof mannuronate alginate subunits to guluronate alginate subunits, whichmay be due primarily to alternating mannuronate-guluronate chains.Recombinant epimerases with different specificities may be used totailor mechanical and transport characteristics of the alginate.

The solubility and water-holding capacity of the alginate may depend atleast on pH, molecular weight, ionic strength, and the nature of theions present. Alginate tends to precipitate below a pH of about 3.5.Alginate with lower molecular weight calcium alginate chains of lessthan 500 subunits shows increasing water binding with increasing size.Lower ionic strength of alginate increases the extended nature of thecalcium alginate chains. An alginate gel may develop rapidly in thepresence of divalent cations like Ca²⁺, Ba²⁺, Sr²⁺, or Mg²⁺ and acidgels may also develop at low pH. Gelling of the alginate premix mayoccur when divalent cations take part in the interchain ionic bindingbetween guluronate alginate subunit blocks in the polymer chain, givingrise to a three-dimensional network. Alginates with a high content ofguluronate alginate subunit blocks may tend to produce stronger gels.Gels made of mannuronate-rich alginate may be softer and more fragile,with a lower porosity, due in part, for example, to a lower bindingstrength between the polymer chains and to a greater flexibility of themolecules. An alginate gel (a gel coating and/or a gel-based implantbody of an implant) may include a matrix of mannuronate alginatesubunits and guluronate alginate subunits in a predetermined ratiowithin cross-linked chains to provide the desired mechanical strengthand flexibility while controlling the elution rates for therapeuticagents (see Section II).

The gelling process may be highly dependent on diffusion of gelling ionsinto the polymer network. Methods that may be used for the preparationof alginate gels may include dialysis/diffusion and internal gelling.

In the dialysis/diffusion or diffusion-setting method, gelling ions maybe allowed to diffuse into the alginate solution. This method may beused for immobilization of living cells in the alginate gel. An alginatesolution can also be solidified by internal gelation, internal setting,or in situ gelling. A calcium salt with limited solubility or complexeddivalent calcium ions may be mixed into an alginate solution, resultingin the release of calcium ions, usually by the generation of acidic pHwith a slowly acting acid such as D-glucono-α-lactone. The resultantalginate may be a homogeneous alginate macrogel. Diffusion setting andinternal setting of the alginate matrix may have different gellingkinetics and may result in differences in gel networks.

II. Therapeutic Agents

Implants of the present teachings may be configured to serve as a sourceof therapeutic agents released from a gel of the implants. Thetherapeutic agents may be released from the gel with any suitablekinetics over any suitable time period, such as minutes, hours, days,weeks, months, years, etc. Release of the agents may occur throughdiffusion from the gel, fluid flow through the gel, breakdown of theimplants (such as by bio-erosion of the gel and particularly a matrixthereof), lysis of cells in the matrix, secretion from cells in thematrix, and/or the like.

The therapeutic agents may have any suitable relationship to sourcecomponents included in the gels. The therapeutic agents may bestructurally identical to the source components, chemical derivatives ofthe source components (such as derivatives produced by cleavage,oxidation, reduction, addition, cyclization, isomerization, and/orremoval of moieties from the source components), and/or products of thesource components (such as metabolites of cells).

The source components may be introduced into gels by any suitableapproach. For example, the source components may be (1) present during,and trapped/encapsulated by, gel matrices during their formation, and/or(2) introduced after matrix formation (such as by diffusion by soakingthe gels in solutions containing the source components). The sourcecomponents thus may be retained noncovalently or covalently by gelmatrices. Covalently retained source components may be bonded to gelmatrices before, during, and/or after formation of the matrices. Forexample, the source components may be bonded to polymer chains beforeand/or after the chains are cross-linked to form gel matrices.

One or more source components disposed in a gel may be therapeuticcomponents (chemical substances) and/or cellular components (cells) thatact as a source of one or more therapeutic agents. Therapeutic agentsreleased from a gel coating and/or a gel implant body may include, forexample, nitric oxide, vascular endothelial growth factor, a biologicalanti-inflammatory agent, vitamin C, acetylsalicylic acid, a lipidlowering compound, a high-density lipoprotein cholesterol, astreptokinase, a kinase, a thrombolytic agent, an anti-thrombotic agent,a blood-thinning agent, a coumadin material, an anti-cancer agent, anangiogenic agent, an anti-angiogenic agent, an anti-rejection agent, ahormone, a therapeutic component, a cellular component, or a combinationthereof.

A. Therapeutic Components

In some embodiments, therapeutic components may be dispersed within agel coating and/or gel-based implant body of an implant. Therapeuticcomponents within a gel coating or implant body may be any suitablesubstance, including, for example, an anti-coagulant, an anti-plateletdrug, an anti-thrombotic drug, an anti-proliferant, an inhibitory agent,an anti-stenotic substance, heparin, a heparin peptide, an anti-cancerdrug, an anti-inflammatant, nitroglycerin, L-arginine, an amino acid, anutraceutical, an enzyme, a nitric oxide synthase, a diazeniumdiolate,matrix metalloproteinase, a nitric oxide donor, rapamycin, a rapamycinanalog, paclitaxel, a paclitaxel analog, a coumadin therapy, a lipase,or a combination thereof. Therapeutic agents released from a gel havingtherapeutic components may include, for example, the componentsthemselves and/or derivatives thereof.

Since it is such a small molecule, nitric oxide can diffuse rapidlyacross cell membranes and, depending on the conditions, is able todiffuse distances of more than several hundred microns, as isdemonstrated by its regulation of smooth muscle cells, vasculardilation, tissue compliance and physiological tone of the vessel. Nitricoxide may be produced within a gel matrix, such as an alginate matrixconfigured as a gel coating and/or gel-based implant body, and thendelivered directly to a vessel. For example, L-arginine, a naturallyoccurring amino acid, and/or other nutraceuticals may be converted tonitric oxide within an alginate or other gel matrix by a group ofenzymes such as nitric oxide synthases. These enzymes convert L-arginineinto citrulline, producing nitric oxide in the process. In anotherexample, nitric oxide is liberated from diazeniumdiolates, compoundsthat release nitric oxide into the blood stream and vascular walls.

B. Cellular Components

Cellular components within a gel coating and/or gel-based implant bodymay include any suitable living or dead cells of one or more types. Thecells may be, for example, endothelial cells, manipulated cells ofdesigner deoxyribonucleic acid, host-derived cells from a host source(that is, from the intended recipient of a stent or other implant),donor-derived cells from a donor source (other than the recipient),pharmacologically viable cells, freeze-dried cells, or a combinationthereof. Therapeutic agents released from a gel having cellularcomponents may include, for example, a residue, a byproduct, and/ornatural secretion from the cells.

In some examples, the cellular components may include endothelial cellsthat produce nitric oxide, a regulating molecule for smooth muscle cellquiescence and maintenance of vascular smooth muscle cells in thenon-proliferative stage. A patient's own endothelial cells from, forexample, microvascular adipose tissue may be harvested and mixed with apre-gel solution (such as a fluent alginate solution). The cells thenmay be encapsulated in the gel produced by gelation. This gel may beformed on a medical implant (such as a coating on a stent) and/or mayform at least a substantial portion of the implant. Upon implantation,the cells may remain viable (living) and locally may produce nitricoxide to regulate and maintain the quiescent nature of smooth musclecells, which can be a contributor to the production and recruitment offibroblasts from the media and adventitia of arteries. With thecontinued long-term production of nitric oxide from translocatedendothelial cells, vascular patency may be maintained for a periodsubstantially longer than the period for potential stenotic reoccurrencefollowing stent placement.

In some examples, cells, such as endothelial cells, from either a hostor donor source may be preserved with trehalose and freeze-dried,rendering the cells functional yet in a dehydrated state. The cells maybe mixed into an alginate solution (or other pre-gel solution) and thenused to coat an implant and/or form the implant body of the implant. Useof cells in a preserved fashion may allow for manufacturing of animplant in advance of a medical procedure. The cells may be preservedwith trehalose and protected by the immune barrier of the alginate orother gel matrix. One skilled in the art can identify alternativecell-producing components that can be substituted for endothelial cellsand provide therapeutic agents from a gel matrix.

In the case of cellular components, a gel matrix (such as an alginatematrix) may serve as an immune barrier so that the immune system of therecipient does not recognize cellular components contained within thegel matrix. Accordingly, the immune system may be restricted fromkilling and/or destroying the cells and thus terminating the productionof therapeutic agents by the cells. In addition, the gel matrix mayallow for the passage of nutrients, wastes, and therapeutic proteins andagents through the gel matrix into the surrounding vessel (and/or fromthe vessel into the matrix). Therapeutic agents thus may be delivered inclose proximity to the treatment site. With imbibed cellular andtherapeutic components, long-term release of therapeutic agents from thegel coating may be provided.

Living cells or other biomaterials and therapeutic compounds may beimmobilized in an alginate matrix. Cells immobilized in alginate gelsmay maintain good viability during long-term culture, due in part to themild environment of the gel network. An alginate gel may provide aphysically protective barrier for immobilized cells and tissue, and mayinhibit immunological reactions of the host.

An alginate matrix may provide a location that is viable and productivefor cellular components. This viable and productive location may bepossible because an alginate matrix allows diffusion of nutrients tocells, diffusion of respiratory byproducts to the surrounding area, anddiffusion of selected therapeutic components in an unaltered conditionfrom the alginate matrix. In some cases, an alginate matrix may serve asan immune barrier while providing for diffusive transport fortherapeutic and cellular materials. The immune barrier properties of analginate matrix may be particularly useful for non-host derived cellsources, or manipulated cells of designer deoxyribonucleic acid (DNA).

III. Gel-Coated Implants

Implants of the present teachings may include an implant body and a gelcoating disposed partially or at least substantially completely over thesurface of the body.

FIG. 1 illustrates an example of a coated implant, such as a coatedstent, constructed in accordance with aspects of the present teachings.FIG. 2 illustrates a cross-sectional view of the coated implant of FIG.1, with like-numbered elements referring to similar or identicalelements in each illustration. Coated stent 10 may include a stentlatticework 20 with an alginate or other gel-based coating 30 disposedon stent latticework 20. Alginate coating 30 may provide a protectivecoating for stent latticework 20 to minimize, for example, emission ofmetal ions. Alginate coating 30 also may provide a mechanism forcontrolled, time-release characteristics of therapeutic agents 40 fromany therapeutic components 34 and cellular components (cells) 36disposed within an alginate matrix 32 of alginate coating 30. In someexamples, the present teachings may provide localized delivery of one ormore therapeutic agents 40 from therapeutic components 34 dispersedwithin alginate coating 30 when coated stent 10 is deployed (positionedand/or expanded) within a lumen of a mammalian recipient. In someexamples, the present teachings may provide long-term delivery of one ormore therapeutic agents 40 via a matrix suitable for encapsulatingliving (and/or dead) cells from transplanted or implanted cells thatproduce such therapeutic agents.

Stent latticework 20 or other implantable medical devices may be coveredwith a relatively thin coating of alginate matrix 32 including selectedtherapeutic components 34 and cellular components 36 that producetherapeutic agents 40 for elution from alginate coating 30. The alginatecoating thus may serve as a source of these therapeutic agents.

Stent latticework 20 of coated stent 10 may comprise, for example, ametallic body or a polymeric body. Metallic bodies generally may beformed of any biocompatible metal or metal alloy, including stainlesssteel, nitinol, platinum, and/or titanium, among others. Polymericbodies may include, for example, a non-absorbable polymer, such aspolyethylene, and/or a bio-absorbable polymer such as poly-lactide,poly-galactide, lactide/galactide co-polymers, polydioxanones, and/orother bio-erodable polymers suitable for implantation within a mammalian(such as human) body.

Stent latticework 20 of coated stent 10 may be, for example,balloon-expandable or self-expandable, which are stent configurationsthat are well known in the art. Balloon-expandable stents may be crimpedonto an inflatable polyurethane balloon that is coupled near a distalend of a catheter body. Inflation lumens within the catheter body mayallow an inflation fluid to be transported into and out from an interiorregion of the inflatable balloon. When coated stent 10 is appropriatelypositioned within the vessel, the stent may be expanded by inflating theballoon, thereby enlarging stent latticework 20 and deforming thelatticework against the endoluminal wall of the vessel to providemechanical support and allow for elution of one or more therapeuticagents 40 from alginate coating 30.

Alternatively, a self-expandable stent latticework 20 may expand andpress against endoluminal walls of the vessel, for example, when acompression retainer such as a deployment sheath is pulled away from thestent latticework so that the compressed stent latticework freelyexpands towards its original expanded shape.

Gel coating 30 may include an alginate matrix 32, and may include one ormore therapeutic components 34 and/or cellular components 36. Gelcoating 30 may be configured to control the elution (release) of one ormore therapeutic agents 40 from either therapeutic components 34 orcellular components 36 in the coating.

In some embodiments, coated stent 10 may include one or more cellularcomponents 36 dispersed within alginate coating 30. Cellular components36 and the gel matrix may be configured so that therapeutic agent 40 isreleased when coated stent 10 is deployed within a vessel of a mammalianbody, for example by diffusion and/or cleavage of chemical bonds, amongothers.

In some examples, long-term administration of at least one therapeuticagent 40 such as nitric oxide may be provided by an implant to amammalian vessel. Endothelial-derived nitric oxide is a naturallyoccurring regulation compound. The endothelial cell lining of vesselsproduces the nitric oxide molecule. Endogenously produced nitric oxideis produced by the endothelial cell in such a manner that the uptake ofthe molecule regulates the proliferation of the vascular smooth musclecells and maintains the cellular quiescence of smooth muscle cellswithin the vascular architecture. Nitric oxide may be critical tonumerous biological processes, including vasodilation,neurotransmission, and macrophage-mediated microorganism and tumorkilling. Nitric oxide may be administrated in a chemically synthesizedform as a nitric oxide donor, such as nitroglycerin dispersed withinalginate matrix 32.

Disruption of the endothelial lining in the vessel may result in thereduction of nitric oxide production, leading to the loss of regulationof the smooth muscle cells. This disruption can occur during stentplacement, angioplasty, or from disease accumulation. Stent placementand angioplasty procedures that open an occluded vessel exertsignificant pressure on the luminal surface and may damage theendothelial cells.

FIG. 2 illustrates a sectional view of the coated stent of FIG. 1, takenthrough line A-A′. Coated stent 10 may include a stent latticework 20and an alginate coating 30 disposed on stent latticework 20. Sincealginate coating 30 may be thin relative to the spacing between strutsof stent latticework 20. Alginate coating 30 may individually coat thestruts and/or other members of stent latticework 20.

Alginate coating 30 may include an alginate matrix 32 with one or moretherapeutic components 34 or cellular components 36 dispersed withinalginate coating 30. For example, therapeutic components 34 and cellularcomponents 36 can be either uniformly dispersed throughout alginatecoating 30, or have a non-uniform profile with a higher concentration oftherapeutic components 34 or cellular components 36 nearer the struts ofstent. latticework 20 or closer to an outer surface of alginate coating30. In another example, therapeutic components 34 and cellularcomponents may agglomerate or collect in regions of alginate coating 30.

FIG. 3 illustrates a coated stent deployed in a vessel, in accordancewith aspects of the present teachings. In either a balloon-expandable orself-expanding configuration, a coated stent 10 with a stent latticework20 and an alginate coating 30 may be deployed in a vessel 50 of amammalian body 52. Vessel 50 may have a partial occlusion or stenosedregion 54 that blocks the flow of fluid through vessel 50. With coatedstent 10 deployed in stenosed region 54, endoluminal walls 56 may belocally expanded outward to reduce the constriction and allow forincreased fluid flow through the vessel.

Alginate coating 30 includes an alginate matrix 32 and one or moretherapeutic components 34 or cellular components 36. Therapeuticcomponents 34 and cellular components 36 act as a source of one or moretherapeutic agents 40 when coated stent 10 is deployed in vessel 50 ofmammalian body 52. Therapeutic agents 40 may elute from alginate coating30 through endoluminal wall 56 of vessel 50 and into various tissues ofstenosed region 54 and vessel 50 near the deployed stent.

FIG. 4 is a schematic diagram of a method for coating an implantablemedical device with a gel, in accordance with aspects of the presentteachings. An alginate or other gel-based coating 30 for an implantablemedical device 12 may include an alginate (or other gel) matrix 32 and atherapeutic component 34 dispersed within alginate matrix 32.Alternatively, or in addition, alginate coating 30 for implantablemedical device 12 includes alginate matrix 32 and cellular component 36dispersed within alginate matrix 32. Alginate coating 30 may contain oneor more therapeutic components 34 and cellular components 36 dispersedwithin alginate matrix 32.

Alginate coating 30 is formed or otherwise deposited on exposed portionsof implantable medical device 12 to provide, for example, mechanicalprotection and controlled, time-release delivery of therapeutic agents40 from either therapeutic components 34 or cellular components 36dispersed within alginate coating 30. In some embodiments, alginatecoating 30 with alginate matrix 32 may encapsulate and maintain theviability of cellular components 36, allowing therapeutic agents 40produced by the cells to pass through alginate matrix 32 and elute intosurrounding target tissues such as arterial tissues.

A ratio of mannuronate alginate subunits 62 and guluronate alginatesubunits 64 may be selected to provide a predetermined elutioncharacteristic of the alginate coating.

An alginate premix of mannuronate alginate subunits 62 and guluronatealginate subunits 64 (in any suitable polymerized (or nonpolymerized)form), an alginate solvent 66 such as alcohol or water, and one or moretherapeutic components 34 and cellular components 36 may be combined toform an alginate solution with the determined ratio of mannuronatealginate subunits 62 and guluronate alginate subunits 64, in a fluentform. The alginate subunits may be provided as polymer chains (generallynot yet substantially cross-linked) or shorter oligomers (or individualsubunits). The term “monomer” as used herein, is intended to mean asubunit moiety, whether the subunit moiety is part of a linear polymerchain, a three-dimensional network, or not linked to other subunits. Analginate linking agent 68 may be added to alginate solution 60, tocross-link the chains. Implantable medical device 12 such as a stentlatticework may be coated with alginate solution 60, where the alginategels to form a gel coating on external surfaces of implantable medicaldevice 12.

Alginate coating 30 may be coated onto implantable medical device 12 (animplant) such as a stent, a valve, a pacemaker lead, a pacemaker, apacing device, a venous filter, an abdominal aortic abdominal aneurysmdevice, or a vascular graft. Alternatively, a gel, such as alginate mayform the implant body of an implant.

FIG. 5 is a flow diagram of a method of treating a vessel in a mammalianbody, in accordance with one embodiment of the present invention.Treatable vessels include, for example, a coronary vessel, acardiovascular vessel, a carotid artery, a hepatic vein, a hepaticartery, an artery, a vein, a peripheral vessel, an esophagus, a bileduct, a trachea, an intestine, a urethra, or a colon. The methodincludes various steps to form a coated stent or other implantablemedical device and to treat or prevent a medical condition in thevessel. Fabrication of the coated stent may occur remotely to, or insome cases, within a clinical setting so that cells may be harvestedfrom a donor or recipient and combined with the coating materialimmediately prior to implantation of the device in the recipient.

A stent latticework is provided, as seen at block 80. The stentlatticework may be balloon-expandable or self-expandable, and may have astent body including a metal such as stainless steel, nitinol, platinum,or a biocompatible metal alloy. Alternatively, the stent latticework mayhave a polymeric body comprised of a polymer such as poly-L-lactide. Thelength, expanded diameter, and compressed diameter of the stent may beselected in accordance with the vessel to be stented.

The desired therapeutic components and/or cellular components may beselected, as seen at block 82. Selectable therapeutic components andcellular components may include any combination of the componentsdescribed elsewhere in the present teachings.

Based on the desired elution characteristics of therapeutic agents fromthe therapeutic and cellular components, the ratio of mannuronatealginate monomers and guluronate alginate monomers may be determined.For example, the block length of mannuronate alginate subunits and theblock length of guluronate alginate subunits may be selected to achievesuitable strength and flexibility of the coated device, while providingcontrolled delivery of therapeutic agents from the therapeutic andcellular components dispersed within the alginate matrix. The dose andconstituency of added therapeutic and cellular components may beselected based on the desired treatment of the vessel.

In some examples, an alginate premix may be sterilized by its passagethrough a selection of submicron filters, by exposure to radiation inthe form of ionizing gamma or electron beams, or by other known methodsof rendering a viscous solution sterile. The premix may be mixed in asolution prior to filtration and then dried, for example, by dialysis orspray drying.

In another example, the mannuronate alginate subunits, guluronatealginate subunits, and an alginate solvent such as alcohol or water maybe mixed to form the alginate solution with the determined ratio ofmannuronate alginate subunits and guluronate alginate subunits. Theconcentration and viscosity of the alginate solution may be reduced withthe addition of aqueous cellular or therapeutic components.

In an optional step, one or more viable cell components may be harvestedfrom a host or donor mammalian body, as seen at block 84. The harvestedviable cellular component comprises, for example, endogenous endothelialcells. The harvested cells may be further cultured to increase theirnumbers or further filtered to obtain the desired quantity, quality, andtype of cell. In some examples, the harvested viable cellular componentmay be mixed into the alginate solution prior to coating the stentlatticework. In some examples, freeze-dried cells may be mixed into thealginate solution with, for example, an aqueous-based alginate solvent.The freeze-dried cells may be reconstituted when the coated stent isinserted and deployed in the mammalian body.

The selected therapeutic components and cellular components may be mixedwith the determined ratio of mannuronate alginate subunits andguluronate alginate subunits or the alginate premix to form the alginatesolution prior to coating the stent latticework, as seen at block 86.For example, endothelial cells may be mixed into a formulation ofalginate with appropriate mannuronate and guluronate components into analginate solution, and the stent is coated with the cellularizedalginate solution.

In some examples, an alginate linking agent is added to the alginatesolution, as seen at block 88. The added alginate linking agentcomprises, for example, divalent calcium, divalent barium, divalentstrontium, divalent magnesium, or a source of calcium such as a calciumsalt. The alginate linking agent may be added to the alginate solutionimmediately prior to coating the stent latticework or other implantablemedical device, due to rapid gelling and setting of the alginate matrix.The alginate matrix is cross-linked, for example, with a divalent-cationsolution such as a calcium solution. In another example, the alginatelinking agent is applied to the stent latticework prior to theapplication of the alginate solution, and as it is applied, the alginatesolution coagulates onto the stent latticework. In another example, thealginate linking agent is applied to a stent latticework previouslycoated with the alginate solution, causing the alginate solution to geland harden accordingly. In another example, alternating alginate layerswith varying ratios of mannuronate and guluronate monomers areincorporated onto the stent latticework, with an optional capping coatthat is abrasion and/or tear-resistant. An alginate linking agent in asolution may be applied, for example, by dipping the alginate-coateddevice in a bath of divalent cation solution or by spraying the divalentcation solution onto the coated stent to initiate cross-linking, gellingand hardening. An alginate coating with multiple layers may be formedfrom successive dips into the same or different alginate solutions.Cross-linking and polymerization of the alginate solution may beactivated at room temperature, or with exposure to ultraviolet light,infrared light, or thermal energy.

The stent latticework is coated with an alginate solution to form acoated stent having an alginate coating disposed on the stentlatticework, as seen at block 90. The alginate coating may include oneor more therapeutic components or cellular components. The stentlatticework may be coated by, for example, spraying, dipping, androlling the stent latticework with the alginate solution at temperaturesbelow, for example, 37 degrees centigrade. The alginate solutionincludes a plurality of alginate monomers and an alginate solvent, andmay include one or more therapeutic components or cellular components.The coated stent is dried and loaded onto a suitable catheter deliverysystem. The resulting device can be sterilized with conventional meansthat do not alter or damage the therapeutic or cellular components orthe alginate matrix.

When used in a medical procedure, the coated stent is positioned withina vessel and deployed, as seen at block 92. Positioning of the coatedstent is accomplished, for example, by coupling the coated stent onto adelivery catheter, and advancing the coated stent to a treatment area byusing a guidewire, as is known in the art. The coated stent is deployed(expanded), for example, by inflating and expanding an inflation ballooncoupled to near the distal end of the catheter, or by retracting asheath from a self-expanding stent latticework.

Once deployed, one or more therapeutic agents may be eluted from thealginate coating, as seen at block 94. The alginate coating controlsaspects of the elution (such as rate, direction, etc.) of thetherapeutic agent when the coated stent is deployed. In one example, theeluted therapeutic agent comprises nitric oxide from entrainedendothelial cells to regulate the proliferation of smooth muscle cellsin the vessel near the deployed stent. In another example, the cellularcomponent in the alginate solution is reconstituted when the coatedstent is deployed, and therapeutic agent is produced and delivered tothe vessel.

IV. Formation of Implants In Situ

Implants (such as stents and/or caps, among others) for vessels or otherlumens may be formed in situ within an implant recipient. The implantsmay, for example, provide support in a vessel (stents) and/or cap orcover plaque (caps).

FIG. 6 illustrates a system for treating a vessel 150 in a mammalianbody 152, in accordance with aspects of the present teachings. Thesystem may include an implant formation catheter 110 having a catheterbody 112. One or more inflatable balloons such as a formation balloon120 may be attached to catheter body 112 near a distal end 114 ofcatheter body 112. An alginate stent 130 (and/or a cap) may be formedfrom an alginate solution 160 injected through an alginate-deliverylumen 118 included within catheter body 112 into a portion 156 of vessel150. Alginate solution 160 is injected into a cavity 122 betweenformation balloon 120 and an endoluminal wall 154 of vessel 150 whenformation balloon 120 is inflated. An alginate cap may be formed, forexample, to treat vulnerable plaque and/or inflamed tissue adjacent alumen. Stents and/or caps may be formed with or without openings intheir walls and may have any suitable thickness. Accordingly, implantsmay provide a support function to keep a vessel (or other lumen) openand/or may release therapeutic agents to the vessel or other tissue.

The formed alginate stent (or other implant) 130 may include a gel, forexample, an alginate matrix (or other gel matrix) 132 in contact withendoluminal wall 154 of vessel 150, and a central lumen 142 axiallyextending through alginate matrix 132.

Formation balloon 120 may have surface features 146 to form at least oneaperture 144 in alginate stent 130 when alginate solution 160 isinjected. Alginate stent 130 may have one or more apertures 144 formedin alginate matrix. Apertures 144 may be positioned between centrallumen 142 of alginate stent 130 and endoluminal wall 154 of vessel 150.Alternatively, the implant may be formed without apertures, such as alining or cap to cover vulnerable plaque.

Inflation lumens within the catheter body 112 allow an inflation fluid148 to be transported from a proximal end 116 of stent formationcatheter 110 into and out of the interior regions of one or moreinflation balloons attached to catheter body 112. When stent formationcatheter 110 is appropriately positioned within vessel 150, exemplaryalginate stent 130 is formed by inflating formation balloon 120,creating a cavity 122 between an outer surface of formation balloon 120and endoluminal wall 154 of vessel 150. A guidewire 108 may be used toposition stent formation catheter 110 at a desired location in mammalianbody 152, as is known in the art. To form a cap, the implant-formationcatheter 10 may have an over-the-wire, rapid exchange, monorail, orother type of catheter configuration, as is known in the art. Analginate solution 160 is injected through a port at proximal end 116,through alginate-delivery lumen 118, and into cavity 122, where ithardens (gels such as by cross-linking) to form alginate stent 130against endoluminal wall 154 of the vessel. Alginate stent 130 providesmechanical support for vessel 150, as well as elutes and locallydelivers one or more therapeutic agents 140.

Alginate stent 130 can support and treat vessel 150 in mammalian body152. Alginate stent 130 may be used, for example, in a coronary vessel,a cardiovascular vessel, a carotid artery, a hepatic vein, a hepaticartery, an artery, a vein, a peripheral vessel, an esophagus, a bileduct, a trachea, an intestine, a urethra, or a colon.

Alginate stent 130 provides a mechanism for controlled, time-releasecharacteristics of therapeutic agents 140 from any therapeuticcomponents 134 and cellular components 136 within an alginate matrix 132of alginate stent 130. In one embodiment, the invention provideslocalized delivery of one or more therapeutic agents 140 fromtherapeutic components 134 dispersed within alginate stent 130 whenalginate stent 130 is formed within a vessel 150 of the mammalianrecipient. In another embodiment, the invention provides long-termdelivery of one or more therapeutic agents 140 via an alginate matrix132 suitable for maintaining encapsulated cells and aggregates of viablecells from transplanted or implanted cells that produce such therapeuticagents.

Alginate stent 130 may include one or more therapeutic components 134and/or cells dispersed within alginate matrix 132. Any suitabletherapeutic components and/or cells may be included. Exemplarytherapeutic components and cells that may be suitable are described inSection II and elsewhere in the present teachings.

Alginate matrix 132 may include selected therapeutic components 134 andcellular components 136 that produce therapeutic agents 140 for elutionfrom alginate matrix 132 of alginate stent 130. When cellular components136 are selected, alginate matrix 132 serves as an immune barrier sothat the immune system of the recipient does not recognize and destroycellular component 136 contained within alginate matrix 132, orterminate the production of therapeutic agents 140. Meanwhile, alginatematrix 132 still allows for the metabolic transfer of nutrients, wastes,and therapeutic proteins and agents to pass through alginate matrix 132into surrounding vessel 150. Therapeutic agents 140 are delivered inclose proximity to the treatment site and released from alginate stent130. Alginate stent 130 with therapeutic components 134 and cellularcomponents 136 provides long-term expression of the therapeutic agents140.

Alginate stent 130 having therapeutic components 134 or cellularcomponents 136 may help prevent restenosis by eluting of one or moretherapeutic agents 140 near the tissue needing treatment. For example,the eluted therapeutic agents may regulate proliferation of smoothmuscle cells in the vicinity of alginate stent 130, or inhibit fibrinformation and growth of neointimal tissue within the treated area ofvessel 150.

Living cells or other biomaterials and therapeutic compounds may beimmobilized in alginate matrix 132 such as an alginate gel. Cellsimmobilized in alginate gels maintain good viability during long-termculture, due in part to the mild environment of the gel network.Alginate gel provides a physically protective barrier for immobilizedcells and tissue, and inhibits immunological reactions of the host.Alginate matrix 132 provides a location that is viable and productivefor cellular components 136, since alginate matrix 132 allows thediffusion of nutrients to the cell, diffusion of respiratory byproductsto the surrounding area, and diffusion of selected therapeuticcomponents 134 in an unaltered condition from alginate matrix 132. Insome cases, alginate matrix 132 serves as an immune barrier whileproviding for diffusive transport for therapeutic and cellularmaterials. The immune barrier properties of alginate matrix 132 areparticularly useful for non-host derived cell sources, or manipulatedcells of designer deoxyribonucleic acid (DNA).

One example of a cellular component 136 is an endothelial cell thatproduces nitric oxide, a regulating molecule for smooth muscle cellquiescence and maintenance of vascular smooth muscle cells in thenon-proliferative stage. A patient's own endothelial cells from, forexample, microvascular adipose tissue, may be harvested and mixed withan alginate solution, and formed along with alginate matrix 132 intoalginate stent 130. Upon implantation, the endothelial cells remainviable and locally produce nitric oxide to regulate and maintain thequiescent nature of smooth muscle cells, which can be a contributor tothe production and recruitment of fibroblasts from the media andadventitia of arteries. With the continued long-term production ofnitric oxide from the translocated endothelial cells, vascular patencymay be maintained for a period substantially longer than the period forpotential stenotic reoccurrence following stent formation.

Long-term administration of at least one therapeutic agent 140 such asnitric oxide may be provided to vessel 150. Disruption of theendothelial lining in vessel 150 may result in the reduction of nitricoxide production, leading to the loss of regulation of the smooth musclecells. This disruption can occur during placement of conventionalstents, angioplasty procedures, or from disease accumulation. Stentplacement and angioplasty procedures that open an occluded vessel exertsignificant pressure on the luminal surface and may damage theendothelial cells.

Since it is such a small molecule, nitric oxide is able to diffuserapidly across cell membranes and, depending on the conditions, is ableto diffuse distances of more than several hundred microns, as isdemonstrated by its regulation of smooth muscle cells, vasculardilation, tissue compliance and physiological tone of the vessel. Nitricoxide may be produced within alginate matrix 132 and delivered directlyto the vessel. For example, L-arginine, a naturally occurring aminoacid, and other nutraceuticals may be converted to nitric oxide withinalginate matrix 132 by a group of enzymes such as nitric oxidesynthases. These enzymes convert L-arginine into citrulline, producingnitric oxide in the process. In another example, nitric oxide isliberated from diazeniumdiolates, compounds that release nitric oxideinto the blood stream and vascular walls.

Alginate stent 130 comprises alginate matrix 132 with, for example,cross-linked chains of mannuronate alginate monomers 162 and guluronatealginate monomers 164. A predetermined ratio of mannuronate alginatemonomers 162 and guluronate alginate monomers 164 can be selected andformed into alginate matrix 132 to provide the desired elution rates fortherapeutic agents 140.

FIG. 7 illustrates a longitudinal view of an exemplary alginate stent,in accordance with one embodiment of the present invention. FIG. 8illustrates an axial sectional view of the alginate stent of FIG. 7,with like-numbered elements referring to similar or identical elementsin each illustration. FIG. 7 and FIG. 8 taken together, an alginatestent 130 includes an alginate matrix 132 and a central lumen 142axially extending through alginate matrix 132. Alginate stent 130 mayinclude one or more therapeutic components 134 and/or cellularcomponents 136. Therapeutic components 134 and cellular components 136may be dispersed uniformly within alginate matrix 132 or have apreferred distribution. Therapeutic agents 140 are eluted from alginatestent 130, wherein alginate matrix 132 controls the elution oftherapeutic agents 140. Alginate stent 130 provides a mechanism forcontrolled, time-release characteristics of therapeutic agents 140 fromany therapeutic components 134 and cellular components 36 within analginate matrix 132 of alginate stent 130. In one embodiment, theinvention provides localized delivery of one or more therapeutic agents140 from therapeutic components 134 dispersed within alginate stent 130when alginate stent 130 is deployed within a vessel of a mammalianrecipient. In another embodiment, the invention provides long-termdelivery of one or more therapeutic agents 140 via a matrix suitable formaintaining encapsulated cells and aggregates of viable cells fromtransplanted or implanted cells that produce such therapeutic agents.

An array of apertures 144 may be included in alginate stent 130 toprovide support for the vessel wall while allowing transport of materialthrough the sides of alginate stent 130.

Alginate stent 130 may have cross-linked chains of mannuronate alginatemonomers 162 and guluronate alginate monomers 164 in a predeterminedratio to provide the desired mechanical strength and flexibility whilecontrolling the elution rates for therapeutic agents 140 from alginatestent 130.

FIG. 8 illustrates an axial cross-sectional view of the alginate stentof FIG. 7, taken through line A-A′. Alginate stent 130 includes analginate matrix 132 that may have one or more therapeutic components 134or cellular components 136 dispersed therein. For example, therapeuticcomponents 134 and cellular components 136 dispersed within alginatestent 130 may be uniformly dispersed throughout, have a non-uniformprofile with a higher concentration of therapeutic components 134 orcellular components 136 nearer the central lumen 142, or have anon-uniform profile with a higher concentration of therapeuticcomponents 134 and cellular components 136 closer to an outer surface ofalginate stent 130. In another example, therapeutic components 134 andcellular components agglomerate or collect in regions within alginatestent 130. One or more apertures 144 may be included in alginate stent130 to provide support for the vessel wall while allowing transport ofmaterial through the sides of alginate stent 130.

FIG. 9 illustrates an alginate stent 130 with a central lumen 142 and aplurality of apertures 144, in accordance with one embodiment of thepresent invention. Alginate stent 130 may have one or more apertures 144formed in an alginate matrix 132 of alginate stent 130, to allow, forexample, the transport of nutrients to and waste materials from vesselor organ walls. An aperture 144 may be included in alginate stent 130 toallow blood or other bodily fluid to flow through, for example, a vesselthat is bifurcated with a branching vessel, which would otherwise beblocked by the formation of a more solid tubular form of alginate stent130. An array of apertures 144 may be included in alginate stent 130 toprovide support for the vessel wall while allowing transport of materialthrough the sides of alginate stent 130. Alternatively, the implant maybe a cap for vulnerable plaque, which may include or lack apertures.

FIG. 10 is a flow diagram of a method for treating a vessel in amammalian body, in accordance with another embodiment of the presentinvention. The method includes various steps to form an alginate stentand to treat or prevent one or more medical conditions in the region ofalginate stent formation. The alginate stent includes an alginatematrix, and one or more therapeutic components and cellular componentsmay be dispersed therein. Treatable vessels include, for example, acoronary vessel, a cardiovascular vessel, a carotid artery, a hepaticvein, a hepatic artery, an artery, a vein, a peripheral vessel, anesophagus, a bile duct, a trachea, an intestine, a urethra, or a colon.Formation of the alginate stent may occur in a clinical setting, so thatdonor-provided cells, for example, may be harvested from a host or donormammalian body and combined into the alginate solution immediately priorto formation of the alginate stent. The harvested cells may be furthercultured to increase their numbers or further filtered to obtain thedesired quantity, quality and type of cells.

The alginate stent is formed within a vessel to provide mechanicalsupport and controlled, time-released delivery of therapeutic agentsfrom either therapeutic components or cellular components dispersedwithin the alginate stent. In one embodiment, the alginate stent with analginate matrix encapsulates and maintains the viability of cellularcomponents, and allows the expression of therapeutic agents from thecells to pass through the alginate matrix and elute into surroundingtarget tissues such as arterial tissues. The alginate matrix andtherapeutic or cellular components may be used in conjunction withvarious medical procedures using vascular devices such as abdominalaortic aneurysm (AAA) devices, venous filters, vascular grafts, andvalves.

Desired therapeutic components and cellular components are selectedalong with the desired quantity, as seen at block 200. Selectabletherapeutic components and/or cellular components may include any of thesource components and/or therapeutic agents described in Section II orelsewhere in the present teachings. Selectable cellular componentsinclude, for example, endothelial cells, designer-DNA manipulated cells,host-derived cells from a host source, donor-derived cells from a donorsource, pharmacologically viable cells, freeze-dried cells, or acombination thereof. The dose and constituency of added therapeutic andcellular components may be selected based on the desired treatment ofthe vessel and the desired elution rate of the therapeutic agents.

A ratio of mannuronate alginate monomers and guluronate alginatemonomers may be determined to provide a predetermined elutioncharacteristic of the alginate stent. Based on the desired elutioncharacteristics of the therapeutic and cellular components, the ratio ofmannuronate alginate monomers and guluronate alginate monomers may bedetermined. For example, the block length of mannuronate alginatemonomers and the block length of guluronate alginate monomers areselected to achieve suitable strength and flexibility of the stent,while providing controlled delivery of therapeutic and cellularcomponents dispersed within the alginate matrix.

Prior to injection and formation of the alginate stent, the alginatepremix, monomers or polymers may be sterilized by passage through aselection of submicron filters, by exposure to radiation in the form ofionizing gamma or electron beams, or by other known methods of renderinga viscous solution sterile. The premix may be mixed in a suitablesolvent prior to filtration and then dried, for example, by dialysis orspray drying.

An alginate solution including an alginate premix and an alginatesolvent is mixed prior to forming the alginate stent, as seen at block202. In one example, the mannuronate alginate monomers, guluronatealginate monomers, and an alginate solvent such as alcohol or water aremixed to form the alginate solution with the determined ratio ofmannuronate alginate monomers and guluronate alginate monomers. Theconcentration and viscosity of the alginate solution may be reduced withthe addition of aqueous cellular or therapeutic components. In anotherexample, the mannuronate alginate monomers, guluronate alginatemonomers, alginate solvent, and the selected therapeutic or cellularcomponents are combined to form the alginate solution with thedetermined ratio of mannuronate alginate monomers and guluronatealginate monomers. For example, endothelial cells are mixed into aformulation of alginate with appropriate mannuronate and guluronatecomponents into an alginate solution, and the alginate solution used toform the alginate stent. In another example, an alginate premix ofmannuronate alginate monomers and guluronate alginate monomers, analginate solvent such as alcohol or water, and one or more therapeuticcomponents and cellular components are combined to form the alginatesolution.

A radiopaque additive such as divalent barium may be added to thealginate solution to improve fluoroscopic and radioscopic visualizationof the alginate solution during formation of the alginate stent withinthe mammalian body. In some examples, the radiopaque additive may be across-linking agent for stimulating gel-formation.

In an optional step, one or more viable cell components may be harvestedfrom the host or a donor mammalian body, and incorporated or otherwisemixed into the alginate solution prior to formation of the alginatestent in the mammalian body, as seen at block 204. The harvested cellsmay be further cultured to increase their numbers or further filtered toobtain the desired quantity, quality and type of cells. The harvestedviable cellular component, such as endogenous endothelial cells, ismixed into the alginate solution prior to injecting the alginatesolution. In another example, freeze-dried cells are mixed into thealginate solution with for, example, an aqueous-based alginate solvent.The freeze-dried cells are reconstituted when the alginate stent isformed within the mammalian body. In another example, cells from eithera host or donor source are preserved with trehalose and freeze-dried,rendering the cells functional yet in a dehydrated state. Use of cellsin a preserved fashion allows for mixing the alginate solution with thecells in advance or conjointly with the medical procedure. One skilledin the art can identify alternative cell-producing components that canbe substituted for endothelial cells and provide therapeutic productsfrom the alginate matrix.

An alginate linking agent is added to the alginate solution, as seen atblock 206. The added alginate linking agent comprises, for example,divalent calcium, divalent barium, divalent strontium, divalentmagnesium, or a source of calcium such as a calcium salt. In oneexample, the alginate linking agent is added to the alginate solutionimmediately prior to injecting the alginate solution, due to rapidgelling and setting of the alginate matrix. In another example, thealginate linking agent is added to the alginate solution after injectingthe alginate solution into the portion of the vessel. In anotherexample, the alginate linking agent is co-injected into a portion of thevessel to form the stent. In another example, the alginate linking agentis injected into the stent-formation cavity and combined with alginatesolution injected from a separate port. In another example, the alginatelinking agent is deposited, applied, diffused, or otherwise transferredto an endoluminal wall of the vessel prior to injecting the alginatesolution into the portion of the vessel. As the alginate solution isinjected, the alginate solution coagulates onto the vessel wall.Cross-linking and polymerization of the alginate solution may occur insitu while at mammalian body temperature, or activated with exposure toultraviolet light, infrared light, or thermal energy.

The alginate solution is injected into a cavity formed within a portionof the vessel, where the alginate solution cross-links, gels, andhardens to form the alginate stent. The alginate stent is formed incontact with an endoluminal wall of the vessel and has a central lumenaxially extending through the alginate stent. The amount of alginatesolution injected into the cavity is related to the length and thicknessof the formed stent.

The alginate solution may be injected into a portion of the vessel witha stent formation catheter. The stent formation catheter is positioned,for example, by advancing the distal end of the stent formation catheterto a treatment site using a guidewire inserted into the vessel, as isknown in the art When the stent formation catheter is positioned, thealginate stent may be formed with one or more formation balloonsattached to the catheter body. The formation balloon may have surfacefeatures to form one or more apertures in the alginate stent when thealginate solution is injected.

Once the alginate stent is formed, one or more therapeutic agents may beeluted from therapeutic or cellular components dispersed within thealginate stent, as seen at block 208. In one example, the elutedtherapeutic agent comprises nitric oxide from entrained endothelialcells to regulate the proliferation of smooth muscle cells in the vesselnear the formed alginate stent. In another example, the cellularcomponent in the alginate solution is reconstituted after thecellularized alginate stent is formed in the vessel, and therapeuticagents are produced and delivered to the vessel from the reconstitutedcellular component. The immune barrier of the alginate matrix protectsthe cellular components. The alginate matrix of the alginate stentcontrols the elution of the therapeutic agent from therapeutic andcellular components within the matrix.

FIG. 11 illustrates a longitudinal sectional view of an alginate stent130 being formed within a vessel 150 of a mammalian body 152, inaccordance with one embodiment of the present invention. Vessel 150 hasa partial occlusion or stenosed portion 156 that blocks the flow offluid through vessel 150. A stent formation catheter 110 with a catheterbody 112 has a dog-boned formation balloon 120 attached to catheter body112 near a distal end 114 of catheter body 112. Dog-boned(dumbbell-shaped), as used herein, means widened at opposing end regionsrelative to a central region disposed between the end regions. Formationballoon 120 is inflated, for example, with contrast fluid or inflationfluid 148 injected into an interior region of formation balloon 120. Analginate-delivery lumen 118 within catheter body 112 delivers analginate solution 160 into a cavity 122 formed between formation balloon120 and an endoluminal wall 154 of vessel 150 when formation balloon 120is inflated. Formation balloon 120 may have surface features to form oneor more apertures 144 in alginate stent 130 when alginate solution 160is injected. Slots, grooves or flexible tubes are used, for example, toguide alginate solution 160 from alginate-delivery lumen 118 into cavity122.

As alginate solution 160 sets and hardens, alginate stent 130 withalginate matrix 132 and a central lumen 142 is formed within vessel 150of mammalian body 152. With alginate stent 130 formed in the stenosedregion, endoluminal walls 154 may be locally expanded outward to reducethe constriction and allow for increased fluid flow through the vessel.

FIG. 12 illustrates a longitudinal cross-sectional view of an alginatestent 130 formed within a vessel 150 of a mammalian body 152, inaccordance with one embodiment of the present invention. Alginate stent130 includes an alginate matrix 132 in contact with an endoluminal wall154 of vessel 150. Therapeutic agents 140 may be eluted from alginatestent 130 from one or more therapeutic components 134 and cellularcomponents 136 dispersed within alginate matrix 132. Eluted therapeuticagents 140 migrate into endoluminal wall 154 and other tissues nearalginate stent 130 to provide desired therapeutic effects. Alginatestent 130 may have one or more apertures 144 formed in alginate matrix132 of alginate stent 130.

FIG. 13 is a flow diagram of a method of forming an alginate stent in avessel of a mammalian body, in accordance with one embodiment of thepresent invention. The method includes various steps to form an alginatestent 130 as described with respect to FIG. 11 and FIG. 12.

Stent formation catheter 110 is positioned within vessel 150, as seen atblock 220. Stent formation catheter 110 has catheter body 112 withalginate-delivery lumen 118. Exemplary catheter body 112 has aninflation lumen for transporting inflation fluid 148 to inflateformation balloon 120, and a guidewire lumen to aid in positioning stentformation catheter 110 within the mammalian body.

Formation balloon 120 attached to catheter body 112 near a distal end114 of catheter body 112 is inflated, as seen at block 222. An inflationfluid or contrast fluid may be injected into formation balloon 120 toinflate and enlarge formation balloon 120.

An alginate solution 160 is injected through alginate-delivery lumen 118into cavity 122 formed between inflated formation balloon 120 andendoluminal wall 154 of vessel 150, as seen at block 224. Alginatesolution 160 is hardened with an alginate linking agent to form alginatestent 130 within vessel 150.

After alginate stent 130 has been formed, formation balloon 120 isdeflated and withdrawn from vessel 150 along with stent formationcatheter 110, as seen at block 226.

FIG. 14 illustrates a longitudinal sectional view of an alginate stent130 being formed within a vessel 150 of a mammalian body 152, inaccordance with another embodiment of the present invention.

Alginate stent 130 is formed in a vessel 150 of mammalian body 152 witha system that includes a stent formation catheter 110 having a catheterbody 112. A distal occlusion balloon 124 is attached to catheter body112 near a distal end 114 of catheter body 112. A proximal occlusionballoon 126 is attached to catheter body 112 proximal to distalocclusion balloon 124. A medial formation balloon 128 is attached tocatheter body 112 between distal occlusion balloon 124 and proximalocclusion balloon 126. An alginate-delivery lumen 118 contained withincatheter body 112 carries alginate solution 160 to treatable portion 156of vessel 150. Alginate stent 130 is formed from an alginate solution160 injected through alginate-delivery lumen 118 into a cavity 122between medial formation balloon 128 and an endoluminal wall 154 ofvessel 150 when distal occlusion balloon 124 and proximal occlusionballoon 126 are inflated with an inflation fluid 148. Slots, grooves orflexible tubes may be used to guide alginate solution 160 fromalginate-delivery lumen 118 into cavity 122. Medial formation balloon128 may have surface features (not shown) to form one or more aperturesin alginate stent 130 when alginate solution 160 is injected.

FIG. 15 illustrates a longitudinal sectional view of an alginate stent130 formed within a vessel 150 of a mammalian body 152, in accordancewith another embodiment of the present invention. Alginate stent 130includes an alginate matrix 132 in contact with an endoluminal wall 154of vessel 150, and may include one or more therapeutic components 134 orcellular components 136. Therapeutic agents 140 are eluted fromtherapeutic components 134 and cellular components 136 dispersed withinalginate matrix 132 of alginate stent 130. Therapeutic agents 140 elutefrom alginate stent 130 (inward) into the vessel lumen and/or (outward)through endoluminal wall 154 of vessel 150 and into various tissues ofvessel 150 near formed alginate stent 130. Alginate stent 130 may haveone or more apertures 144 formed in an alginate matrix 132 of alginatestent 130.

FIG. 16 is a flow diagram of various steps of a method of formingalginate stent 130 in vessel 150 of mammalian body 152, in accordancewith another embodiment of the present invention, and as described withrespect to FIG. 14 and FIG. 15. Stent formation catheter 110 ispositioned in vessel 150, as seen at block 240. Stent formation catheter110 has catheter body 112, alginate-delivery lumen 118, and a pluralityof inflation lumens.

Distal occlusion balloon 124 attached to catheter body 112 near distalend 114 of catheter body 112 is inflated, as seen at block 242. Proximalocclusion balloon 126, which is attached to catheter body 112 proximalto distal occlusion balloon 124, is inflated. Medial formation balloon128 attached to catheter body 112 between distal occlusion balloon 124and proximal occlusion balloon 126 is inflated. Distal occlusion balloon124 and proximal occlusion balloon 126 are inflated to occlude vessel150. Medial formation balloon 128 inflates to a diameter correspondingto the desired lumen diameter of alginate stent 130.

Alginate solution 160 is injected through alginate-delivery lumen 118into cavity 122 formed between inflated distal occlusion balloon 124,inflated proximal occlusion balloon 126, inflated medial formationballoon 128, and endoluminal wall 154 of vessel 150, as seen at block244. Alginate solution 160 hardens with an alginate linking agent toform alginate stent 130 within vessel 150.

When alginate stent 130 forms, distal occlusion balloon 124, proximalocclusion balloon 126, and medial formation balloon 128 are deflated,and stent formation catheter 110 is withdrawn from vessel 150, as seenat block 246.

FIGS. 17 a-f illustrate longitudinal sectional views of an alginatestent corresponding to steps of a method for forming an alginate stent130, in accordance with another embodiment of the present invention. Theillustrative steps are performed with an alginate stent formation systemto treat a stenosed portion 156 a vessel 150 in a mammalian body 152.The system includes a stent formation catheter 110 having a catheterbody 112. An angioplasty balloon 170 is attached to catheter body 112near a distal end 114 of catheter body 112. Angioplasty balloon 170 hasan alginate linking agent 168 disposed on a surface 172 of angioplastyballoon 170. A formation balloon 120 is attached to catheter body 112proximal to angioplasty balloon 170. An alginate-delivery lumen 118 isincluded within catheter body 112. An alginate stent 130 is formed froman alginate solution 160 injected through alginate-delivery lumen 118into a cavity 122 between formation balloon 120 and an endoluminal wall154 of vessel 150 when formation balloon 120 is inflated. Formationballoon 120 may have surface features 146 to form at least one aperture144 in alginate stent 130 when alginate solution 160 is injected.

Vessel 150 in mammalian body 152 having endoluminal wall 154 and one ormore stenoses that locally block or restrict the flow of bodily fluid isillustrated in FIG. 17a. Stent formation catheter 110 is positioned at afirst location 174 in vessel 150, as seen in FIG. 17 b. Stent formationcatheter 110 has a catheter body 112. A guidewire 108 inserted intomammalian body 152 may be used to guide stent formation catheter 110 tothe desired position in vessel 150, as is known in the art.

Angioplasty balloon 170 attached to catheter body 112 near distal end114 of catheter body 112 is inflated with an inflation fluid 148, asseen in FIG. 17 c. When in contact with endoluminal wall 154, alginatelinking agent 168 disposed on surface 172 of angioplasty balloon 170 isdeposited on or otherwise transferred to endolurninal wall 154 of vessel150. In an alternative embodiment, alginate linking agent 168 ispre-deposited on an outer surface of formation balloon 120, andtransferred onto endoluminal wall 154 when formation balloon 120 isinflated.

Angioplasty balloon 170 is deflated, and stent formation catheter 110 isrepositioned at a second location 176 in vessel 150, as seen in FIG. 17d. Second location 176, in this example, is distal to first location174.

Angioplasty balloon 170 is re-inflated, as seen in FIG. 17 e.Re-inflated angioplasty balloon 170 serves as a distal protectiondevice. Formation balloon 120 attached to catheter body 112 proximal toangioplasty balloon 170 is inflated. Alginate solution 160 is injectedthrough alginate-delivery lumen 118 into a cavity 122 formed betweenformation balloon 120 and endoluminal wall 154 of vessel 150. Slots,grooves or flexible tubes are used, for example, to guide alginatesolution 160 from alginate-delivery lumen 118 into cavity 122. Alginatesolution 160 flows around or through any surface features 146 to formapertures 144. Alginate solution 160 is hardened, for example, byalginate linking agent 168 deposited on endoluminal wall 154 of vessel150.

Angioplasty balloon 170 and formation balloon 120 are deflated andwithdrawn from vessel 150, as seen in FIG. 17 f. Angioplasty balloon 170may be configured to capture any embolic particles 178 when angioplastyballoon 170 and formation balloon 120 are deflated.

FIG. 18 illustrates a longitudinal sectional view of an alginate stent130 formed within a vessel 150, in accordance with another embodiment ofthe present invention. Alginate stent 130 includes an alginate matrix132 in contact with an endoluminal wall 154 of vessel 150. Therapeuticagents 140 are eluted from alginate stent 130 when one or moretherapeutic components 134 and cellular components 136 are includedwithin alginate matrix 132. Eluted therapeutic agents 140 migrate intoendoluminal wall 154 and other tissues near alginate stent 130 toprovide a therapeutic effect.

FIG. 19 is a flow diagram of steps in a method of, forming alginatestent 130 in vessel 150 of mammalian body 152, in accordance withanother embodiment of the present invention and described with respectto FIG. 17 and FIG. 18.

Stent formation catheter 110 is positioned at first location 174 invessel 150, as seen at block 260. Stent formation catheter 110 includescatheter body 112 with alginate-delivery lumen 118.

Angioplasty balloon 170 attached to catheter body 112 near distal end114 of catheter body 112 is inflated with inflation fluid 148, as seenat block 262. Angioplasty balloon 170 has alginate linking agent 168disposed on surface 172 of angioplasty balloon 170. Alginate linkingagent 168 is deposited or otherwise transferred onto endoluminal wall154 of vessel 150.

Angioplasty balloon 170 is deflated by withdrawing inflation fluid 148from an interior region, as seen at block 264.

With angioplasty balloon 170 deflated to a reduced diameter, stentformation catheter 110 is repositioned at second location 176 locateddistally with respect to first location 174 in vessel 150, as seen atblock 266. Angioplasty balloon 170 is re-inflated. Re-inflatedangioplasty balloon 170 may serve as, for example, a distal protectiondevice. A formation balloon 120 attached to catheter body 112 proximalto angioplasty balloon 170 is then inflated.

Alginate solution 160 is injected through alginate-delivery lumen 118into cavity 122 formed between formation balloon 120 and endoluminalwall 154 of vessel 150, as seen at block 268. Alginate solution 160 ishardened or otherwise set to form alginate stent 130. Alginate linkingagent 168 previously deposited onto endoluminal wall 154 of vessel 150hardens alginate solution 160.

When alginate stent 130 is formed and hardened, angioplasty balloon 170and formation balloon 120 are deflated and withdrawn from vessel 150, asseen at block 270. In one embodiment, angioplasty balloon 170 capturesembolic particles 178 in a region of vessel 150 between angioplastyballoon 170 and formation balloon 120 when angioplasty balloon 170 andformation balloon 120 are deflated. For example, a proximal end ofangioplasty balloon 170 encloses embolic particles 178 when deflated,and a distal end of formation balloon 120 encompasses the proximal endof angioplasty balloon 170 to retain embolic particles 178 while stentformation catheter 110 is being withdrawn. In another example, theproximal end of angioplasty balloon 170 includes a non-mobilecalcium-rich surface that coagulates or cross-links any alginateresiduals, effectively capturing the residuals. Alternatively, embolicparticles 178 may be aspirated out of vessel 150, as is known in theart.

V. Formation of Bioreactors In Situ

This section describes formation of bioreactors in situ in a mammalianbody.

A. Introduction

Various systems and therapeutic agents continue to be developed forimproved long-term delivery of pharmacological and cellulartherapeutics. Pills and injections are often ineffective means ofadministration for long-term treatments because constant drug deliveryand higher local concentration are difficult to achieve via these means.Through repeated doses, drugs often cycle through concentration peaksand valleys, resulting in time periods of toxicity and ineffectiveness.In addition, dosages may be dispersed through the human body rather thanbeing directed to a specific area where the treatment is needed.

Local and longer-term delivery of pharmacological and cellular agents attherapeutically effective levels is desirable for a number of medicalprocedures including those when medical devices are placed permanentlywithin a human body. Drug-eluting coatings or sheaths for vascularstents, for example, are being developed to provide focused, local drugdelivery. To increase the effectiveness of inhibitory drugs that areused for angioplasty and stent procedures, a relatively large number ofdrug molecules may need to be delivered into the intercellular spacesbetween smooth muscle cells of a vessel so that a therapeuticallyeffective dose of molecules can cross cell membranes. The drug dosagemay be difficult to control and direct into the proper intracellularcompartments for treatment while minimizing intercellular redistributionof the drug throughout the body via the vascular system.

Long-term in-vivo cellular therapies are also being proposed as analternative to traditional drug-delivery methods that use oral,intravascular or intramuscular introduction. For medical conditionswhere a person is unable to produce certain cells or the cells have beendamaged, cellular therapeutics may provide long-term therapy. Cellulartherapeutics employ living cells that deliver ameliorating natural orengineered biochemicals, or serve as full-scale replacements fordefective tissues.

An early example and still widely used complex cellular therapeutics ishuman bone marrow transplantation as part of a defined treatment regimeagainst leukemia. Since the late 1960s, bone marrow cells have been usedto replace the chemotherapy-destroyed marrow of patients afflicted withcancer. These marrow cells can be derived either autologously from thepatient before chemotherapy, or from other tissue donors. In some cases,cell therapies involve xenotransplantation of biological implants fromcompletely different species.

A result of non-autologous transplantation is often the lifetime use ofimmunosuppressive drugs, unless the immune system can be retrained ordiverted into accepting the new cells. For example, with pancreaticislet cell transplants, marrow cells from the donor of the islet cellsare also transplanted into the host, thereby signaling the host immunesystem to modify itself and to accept the islet cells.

One proposed approach for eliminating the risk of cells being rejectedby the host or the need to use anti-rejection drugs is to encapsulatecells in biocompatible polymeric substances. Intense study in animalmodels and human clinical trials have recently focused on encapsulatingliving cells for complex therapeutics, with clinical potential for thetreatment of a wide range of diseases.

Cell microencapsulation is a technology where a living cell is infusedor implanted in a microcapsule, which protects the cell from the immunesystem. A microcapsule needs sufficient permeability so that nutrientsand oxygen can reach the transplanted cells, and appropriate cellularproducts, such as insulin from islet cells, can be released into thebloodstream or to adjacent tissues. At the same time, the capsularmaterial should be restrictive enough to exclude immune cells andantibodies that can cause rejection and destroy the implant.

Various types of natural and synthetic polymers, particularly thosehaving a semi-permeable aqueous characteristic, are being explored asencapsulation material. The success of an encapsulation materialdepends, at least in part, on its stability, chemical definability, lackof toxicity, permeability to oxygen and nutrients as well as thereleased therapeutic compounds, and its resistance to antibodies orcellular attack.

Materials for potential polymeric encapsulation systems includepolysaccharide hydrogels, chitosan, calcium alginate or barium alginate.Photopolymerizable poly(ethylene glycol) (PEG) polymer and polyacrylatessuch as hydroxyethyl methacrylate methyl methacrylate, also have beenproposed encapsulant materials. One encapsulation system employsphotolithography techniques to encapsulate living cells in siliconnanocapsules, which have pores of a few nanometers.

A primary purpose for recent research on biocompatible semi-permeablemembranes is to create a protective structure around therapeutic cellsthat grow in vivo and act as a miniature artificial organ or cellfactory within the host body. The survival of encapsulated cellsrequires direct vascularization of the cells along with necessarynutrition and effective protection of the cells from the immune system.In some clinical applications, it is important for a cellular factory tobe positioned within close proximity to its target such that the therapyproduced by the cells is precisely targeted.

Thus, a desirable cell factory needs to have an immune barrier, whileproviding for diffusive transport of nutrients to the cell, respiratorybyproducts from the surrounding area, and selected compounds tosurrounding tissue. The immune barrier properties are requiredespecially for use of non-host derived cell sources or designerdeoxyribonucleic acid (DNA) manipulated cells.

As an exemplary application of bioreactors and cellular factories,electrical insulating coatings for implanted heart pacemakers and otherelectrically conductive medical devices may include therapeutic andcellular components (cells) such as anti-inflammatory or anti-thromboticagents, which are produced in vivo for the prolonged use, therebyincreasing the effectiveness of the device.

Encapsulated cell therapy systems hold promise for a range of cell-baseddelivery for long-term therapeutics that treat diabetes, renal failure,hemophilia, cardiovascular diseases, lysosomal storage diseases,Huntington's disease, ophthalmic disorders, chronic pain,musculoskeletal diseases, hormonal growth deficiencies, solid tumors,and central nervous system diseases such as amyotrophic lateralsclerosis (ALS or Lou Gehrig's disease) and Parkinson's disease. Forexample, encapsulated cells may enable the directed delivery of highlytoxic chemotherapies to cancerous tumors, increasing the options ofusing chemotherapies, which were previously too toxic, in a localizedand localizable fashion. Diabetes is one of the most significant areasof current research for the encapsulation of cells, specifically isletcells of the pancreas that produce insulin. Encapsulated cell therapy isbeing studied for use in gene therapies such as viral vector designerdeoxyribonucleic acid (DNA) from endogenous harvested cells that arevector modified prior to implantation and then implanted.

In cell encapsulation, transplanted cells can be protected from immunerejection by an artificial, semi-permeable membrane such as alginate.Alginate gels have been used in biomedical applications to immobilizeliving cells or other biomaterials, maintaining good cell viabilityduring long-term culture in the mild environment of the gel network.Conventional pharmaceutical-grade alginate, which is low in endotoxinsand other impurities, is extracted from marine brown algae and producedby certain bacteria, for example, Azotobacter vinelandii.

Recently, medical researchers have encapsulated genetically engineeredcells and therapeutic cells in immuno-isolating substances to deliverspecific substances to targeted treatment areas such a brain tumors.Within tissue-engineering applications, immobilized cells or tissues maybe able to serve as bio-artificial organs, while surroundingimmuno-isolating substances function as a protection from physicalstress and immunological reactions with the host. These cell bioreactorshave the potential to excrete biopharmaceuticals and other therapeuticproducts, and are being clinically tested for the treatment of a varietyof diseases like cancer and diabetes. In the case of brain tumors,encapsulated producer cells could be an in-vivo delivery system forspecific proteins that target phenotypic features andmicro-environmental factors, thereby interfering with tumor growth anddifferentiation.

In light of the forgoing discussion, targeted and controlled long-termdelivery of therapeutic drugs, genes or cells, along with theirenscapsulation material still need to be optimized with regard tobiocompatibility, mechanical and chemical stability, suitablepermeability, immune protection for cellular therapeutics, and thetransfer of therapeutic material within a mammalian body.

Successful methods and systems for delivery of cellular therapies areneeded to maintain viable transplanted or implanted cells that producedesirable compounds for extended treatment. Improved long-term deliverysystems for therapeutic agents may be compliant to surrounding tissuesand organs and avoid malapposition of medical devices. Ideally, anencapsulation material and delivery system for various types ofpharmacological, gene, and cell therapies eliminate the need forimmuno-modulatory protocols or immunosuppressive drugs, and permit thelong-term de novo delivery of therapeutic products to either a localizedarea or overall life system.

B. Systems for Forming Bioreactors In Situ

FIG. 20 illustrates an alginate bioreactor 310 for treating a mammalianbody 350, in accordance with one embodiment of the present invention. Acutaway view of an exemplary in-situ formed alginate reactor 310 isshown in the inset. Alginate bioreactor 310 includes an alginate matrix320 and one or more therapeutic components 330 or cellular components332 dispersed within alginate matrix 320. A therapeutic agent 340 iseluted from alginate matrix 320 after alginate bioreactor 310 is formedwithin mammalian body 350. Alginate matrix 320 of alginate bioreactor310 may be formed from an alginate solution 360 injected into a portion352 of mammalian body 350 such as a pancreas. Alginate bioreactor 310may be located in a portion of mammalian body 350 such as a heart, aliver, a pancreas, a kidney, an eyeball, a pericardial space, a cerebralspinal space, a periorganic space, an organ, a vessel, or a tissue.

In one embodiment, the invention provides localized delivery of one ormore therapeutic agents 340 from therapeutic components 330 dispersedwithin alginate bioreactor 310 when alginate bioreactor 310 is formedwithin mammalian body 350 of a mammalian recipient. In anotherembodiment of the invention, one or more therapeutic agents 340 aredelivered long-term from a matrix suitable for maintaining encapsulatedcells and aggregates of viable cells from transplanted or implantedcells that produce such therapeutic agents. In yet another embodiment,one or more therapeutic agents 340 are delivered long-term from analginate matrix 320 that may have one or more therapeutic components 330and one or more cellular components 332 dispersed therein. When alginatematrix 320 is employed, therapeutic components 330 and cellularcomponents 332 may be uniformly dispersed throughout alginate bioreactor310, have a non-uniform profile with a higher concentration oftherapeutic components 330 or cellular components 332 nearer the center,or have a non-uniform profile with a higher concentration of therapeuticcomponents 330 and cellular components 332 closer to an outer surface ofalginate bioreactor 310. In another example, therapeutic components 330and cellular components 332 agglomerate or collect in regions withinalginate bioreactor 310.

Alginate bioreactor 310 is formed from alginate solution 360 that isinjected by an alginate injection system into portion 352 of mammalianbody 350. Formed alginate bioreactor 310 includes an alginate matrix320. A syringe, an adapter catheter, high-pressure jets, or otherinjection techniques may be used to inject alginate solution 360 intothe desired location in mammalian body 350.

Alginate bioreactor 310 elutes and locally delivers one or moretherapeutic agents 340 from therapeutic components 330 and cellularcomponents 332 contained therein to treat medical conditions withinmammalian body 350.

Alginate bioreactor 310 provides a mechanism for controlled,time-release characteristics of therapeutic agents 340 from anytherapeutic components 330 and cellular components 332 within alginatematrix 320 of alginate bioreactor 310. Delivery of therapeutic agents340 may occur over days, weeks, months and even years after formation ofalginate bioreactor 310. With cellular components 332, therapeuticagents 340 may be continuously produced over the lifetime of the host.In one embodiment, the invention provides localized delivery of one ormore therapeutic agents 340 from therapeutic components 330 dispersedwithin alginate bioreactor 310 when alginate bioreactor 310 is formedwithin mammalian body 350 of the mammalian recipient. In anotherembodiment, the invention provides long-term delivery of one or moretherapeutic agents 340 via alginate matrix 320 that is suitable formaintaining encapsulated cells and aggregates of viable cells fromtransplanted or implanted cells that produce such therapeutic agents340.

In one embodiment, alginate bioreactor 310 includes one or moretherapeutic components 330 dispersed within alginate matrix 320, whichcontrols the elution of therapeutic agent 340 from alginate bioreactor310. Therapeutic component 330 includes, for example, an anti-coagulant,an anti-platelet drug, an anti-thrombotic drug, an anti-proliferant, aninhibitory agent, an anti-stenotic substance, heparin, a heparinpeptide, an anti-cancer drug, an anti-inflammatant, nitroglycerin,L-arginine, an amino acid, a nutraceutical, an enzyme, a nitric oxidesynthase, a diazeniumdiolate, a nitric oxide donor, rapamycin, arapamycin analog, paclitaxel, a paclitaxel analog, a coumadin therapy, alipase, a protein, insulin, bone morphogenetic protein, or a combinationthereof. Therapeutic agents 340 released from alginate bioreactor 310include, for example, therapeutic components 330 themselves or portionsthereof.

In another embodiment, one or more cellular components 332 are dispersedwithin alginate matrix 320 of alginate bioreactor 310 to providetherapeutic agent 340. Alginate matrix 320 provides an immune barrierfor cellular components 332 and controls the elution of therapeuticagents 340 from alginate bioreactor 310. Cellular component 332includes, for example, endothelial cells, manipulated cells of designerdeoxyribonucleic acid, host-derived cells from a host source,donor-derived cells from a donor source, pharmacologically viable cells,freeze-dried cells, or a combination thereof. Therapeutic components 330along with cellular components 332 may elute one or more therapeuticagents 340 into surrounding tissue.

Exemplary alginate matrix 320 includes selected therapeutic components330 and cellular components 332 that produce therapeutic agents 340 forelution from alginate matrix 320 of alginate bioreactor 310. Whencellular components 332 are selected, alginate matrix 320 may serve asan immune barrier so that the immune system of the recipient does notrecognize and destroy cellular component 332 contained within alginatematrix 320, or terminate the production of therapeutic agents 340.Meanwhile, alginate matrix 320 still allows for the metabolic transferof nutrients, wastes, and therapeutic proteins and agents to passthrough alginate matrix 320 into surrounding mammalian body 350.Therapeutic agents 340 are delivered in close proximity to the treatmentsite and released from alginate bioreactor 310. Alginate bioreactor 310with therapeutic components 330 and cellular components 332 provideslong-term expression of the therapeutic agents 340.

Therapeutic agents 340 from cellular components 332 include, forexample, a residue, a byproduct, or natural excretion from the cells.One exemplary therapeutic agent 340 is nitric oxide.

Alginate bioreactor 310 having therapeutic components 330 or cellularcomponents 332 may help prevent, for example, inflammation or rupture oftissue by eluting of one or more therapeutic agents 340. For example,eluted therapeutic agents 340 may reduce inflammation in the vicinity ofalginate bioreactor 310 and the area of mammalian body 350 beingtreated.

Alginate bioreactor 310 may take the form of an indwelling filter forvenous applications that incorporate cellular components 332 and elutetherapeutic agents 340 such as streptokinases, kinases or otherthrombolytic agents, coumadin materials or other blood thinning agents,nitrous oxide, and other agents.

Living cells or other biomaterials and therapeutic compounds can beimmobilized in alginate matrix 320 such as an alginate gel. Cellsimmobilized in alginate gels maintain good viability during long-termculture, due in part to the mild environment of the gel network.Alginate gel provides a physically protective barrier for immobilizedcells and tissue, and inhibits immunological reactions of the host.Alginate matrix 320 provides a location that is viable and productivefor cellular components 332, since alginate matrix 320 allows thediffusion of nutrients to the cell, diffusion of respiratory byproductsto the surrounding area, and diffusion of selected therapeuticcomponents 330 in an unaltered condition from alginate matrix 320. Insome cases, alginate matrix 320 serves as an immune barrier whileproviding for diffusive transport for therapeutic and cellularmaterials. The immune barrier properties of alginate matrix 320 areparticularly useful for non-host derived cell sources, or manipulatedcells of designer deoxyribonucleic acid (DNA). Viral transfection ofdesirable DNA can occur outside mammalian body 350 into cellularcomponents 332 that are encapsulated in situ, reducing the possibilityof reaction to the viral vector itself, and allowing for more DNA to betransfected into alginate bioreactor 310.

One example of a cellular component 332 is endothelial cells thatproduce nitric oxide, a regulating molecule for smooth muscle cellquiescence and maintenance of vascular smooth muscle cells in thenon-proliferative stage. A patient's own endothelial cells from, forexample, microvascular adipose tissue, may be harvested and mixed withalginate solution 360, and formed along with alginate matrix 320 intoalginate bioreactor 310. Upon implantation, the endothelial cells remainviable and locally produce nitric oxide to regulate and maintain thequiescent nature of smooth muscle cells, which can be a contributor tothe production and recruitment of fibroblasts from the media andadventitia of arteries. With the continued long-term production ofnitric oxide from the translocated endothelial cells, vascular patencymay be maintained for a substantially longer period following bioreactorformation.

Long-term administration of at least one therapeutic agent 340 such asnitric oxide may be provided to portion 352 of mammalian body 350 thatis diseased or traumatized. For example, disruption of the endotheliallining in a diseased portion of mammalian body 350 may result in thereduction of nitric oxide production, leading to the loss of regulationof the smooth muscle cells. Endothelial-derived nitric oxide is anaturally occurring regulation compound that can be produced by, forexample, the endothelial cell lining of blood vessels. Endogenouslyproduced nitric oxide molecules can regulate the proliferation of thevascular smooth muscle cells and maintain the cellular quiescence ofsmooth muscle cells within the vascular architecture. Nitric oxide isalso critical to numerous biological processes, including vasodilation,neurotransmission, and macrophage-mediated microorganism and killing oftumors. Nitric oxide may be administrated in a chemically synthesizedform as a nitric oxide donor, such as nitroglycerin dispersed withinalginate matrix 320.

Since it is such a small molecule, nitric oxide is able to diffuserapidly across cell membranes and, depending on the conditions, is ableto diffuse distances of more than several hundred microns, as isdemonstrated by its regulation of smooth muscle cells, vasculardilation, tissue compliance and physiological tone of the mammalianbody. Nitric oxide can be produced within alginate matrix 320 anddelivered directly to the mammalian body. For example, L-arginine, anaturally occurring amino acid, and other nutraceuticals are convertedto nitric oxide within alginate matrix 320 by a group of enzymes such asnitric oxide synthases. These enzymes convert L-arginine intocitrulline, producing nitric oxide in the process. In another example,nitric oxide is liberated from diazeniumdiolates, compounds that releasenitric oxide into the blood stream and vascular walls.

Alginate matrix 320 may comprise a predetermined ratio of mannuronatealginate subunits 362 and guluronate alginate subunits 364.

FIG. 21 illustrates a system for forming an alginate bioreactor 310 in aportion 352 of a mammalian body, in accordance with one embodiment ofthe present invention. An alginate bioreactor 310 is being formed withina portion 352 of mammalian body 350 such as a kidney. An alginateinjection system 370 includes a first chamber 372, a second chamber 374,and an alginate solution injector 376, the latter being fluidly coupledto first chamber 372 and second chamber 374. An alginate solution 360from-first chamber 372 is injected into portion 352 of the mammalianbody with an alginate linking agent 368 from second chamber 374 to formalginate bioreactor 310.

Alginate bioreactor 310 within portion 352 of the mammalian bodyprovides directed, localized, time-released delivery of therapeuticagents 340 from therapeutic components 330 and/or cellular components332 dispersed within alginate bioreactor 310. In one embodiment,alginate bioreactor 310 with alginate matrix 320 encapsulates andmaintains the viability of cellular components 332 and allows theexpression of therapeutic agents 340 from the cells to pass throughalginate matrix 320 and elute into surrounding targets such as organs,vessels, and other portions of the mammalian body.

A ratio of mannuronate alginate subunits 362 and guluronate alginatesubunits 364 may be selected to provide a predetermined elutioncharacteristic of alginate bioreactor 310. An alginate premix ofmannuronate alginate subunits 62 and guluronate alginate subunits 364,an alginate solvent 366 such as alcohol or water, and one or moretherapeutic components 330 and cellular components 332 are combined toform alginate solution 360 with the determined ratio of mannuronatealginate subunits 362 and guluronate alginate subunits 364. Alginatelinking agent 368 may be added to alginate solution 360 or maintainedseparately until combined in the mammalian body. When alginate solution360 and alginate linking agent 368 are injected into the mammalian body,the alginate cross-links, gels, and hardens to form alginate bioreactor310. Cross-linking and polymerization of alginate solution 360 may occurin situ while at body temperature, or activated with exposure toultraviolet light, infrared light, or thermal energy.

Alginate solution injector 376, such as a single-lumen syringe, may beused to inject the combined or separated alginate solution 360 andalginate linking agent 368 into the mammalian body. In cases wherealginate solution 360 and alginate linking agent 368 remain separateduntil injected into the mammalian body, a double-lumen syringe may beused for local injection. Alternatively, endoscopic techniques using,for example, guidewires and a bioreactor formation catheter with one ormore delivery lumens, inject alginate solution 360 and alginate linkingagent 368 endoscopically into the mammalian body. Alternatively, ahigh-pressure injection nozzle or a pair of high-pressure injectionnozzles injects alginate solution 360 and alginate linking agent 368into the mammalian body.

The alginate bioreactor may include an alginate matrix and one or moretherapeutic components and cellular components dispersed therein.Formation of the alginate bioreactor may occur in a clinical setting, sothat donor-provided cells, for example, may be harvested from a host ordonor mammalian body and combined into the alginate solution immediatelyprior to formation of the alginate bioreactor.

The alginate bioreactor is formed within a portion of the mammalian bodyto provide controlled, time-released delivery of therapeutic agents fromtherapeutic components and/or cellular components dispersed within thealginate bioreactor. In one embodiment, the alginate bioreactor with analginate matrix encapsulates and maintains the viability of cellularcomponents, and allows the expression of therapeutic agents from thecells to pass through the alginate matrix and elute into surroundingtargets such as arterial tissues, vessels, organs, and periorganicspaces.

Desired therapeutic components and cellular components are selectedalong with the desired quantity. Selectable therapeutic componentsinclude, for example, an anti-coagulant, an anti-platelet drug, ananti-thrombotic drug, an anti-proliferant, an inhibitory agent, ananti-stenotic substance, heparin, a heparin peptide, an anti-cancerdrug, an anti-inflammatant, nitroglycerin, L-arginine, an amino acid, anutraceutical, an enzyme, a nitric oxide synthase, a diazeniumdiolate, anitric oxide donor, rapamycin, a rapamycin analog, paclitaxel, apaclitaxel analog, a coumadin therapy, a lipase, a protein, insulin,bone morphogenetic protein, or a combination thereof. Selectablecellular components include, for example, endothelial cells,designer-DNA manipulated cells, host-derived cells from a host source,donor-derived cells from a donor source, pharmacologically viable cells,freeze-dried cells, and combinations thereof. The dose and constituencyof added therapeutic and cellular components may be selected based onthe desired treatment of the mammalian body and the desired elution rateof the therapeutic agents.

A ratio of mannuronate alginate subunits and guluronate alginatesubunits may be determined to provide a predetermined elutioncharacteristic of the alginate bioreactor, based on the desired elutioncharacteristics of the therapeutic and cellular components. For example,the block length of mannuronate alginate subunits and the block lengthof guluronate alginate subunits are selected to achieve suitablestrength and flexibility of the bioreactor, while providing controlleddelivery of therapeutic and cellular components dispersed within thealginate matrix.

Prior to injection and formation of the alginate bioreactor, thealginate premix, monomers or polymers may be sterilized by passagethrough a selection of submicron filters, by exposure to radiation inthe form of ionizing gamma or electron beams, or by other known methodsof rendering a viscous solution sterile. The premix may be mixed in asuitable solvent prior to filtration and then dried, for example, bydialysis or spray drying.

An alginate solution including an alginate premix and an alginatesolvent is mixed prior to forming the alginate bioreactor. In oneexample, the mannuronate alginate subunits, guluronate alginatesubunits, and an alginate solvent such as alcohol or water are mixed toform the alginate solution with the determined ratio of mannuronatealginate subunits and guluronate alginate subunits. The concentrationand viscosity of the alginate solution may be reduced with the additionof aqueous cellular or therapeutic components. In another example, themannuronate alginate subunits, guluronate alginate subunits, alginatesolvent, and the selected therapeutic or cellular components arecombined to form the alginate solution with the determined ratio ofmannuronate alginate subunits and guluronate alginate subunits. Forexample, endothelial cells are mixed into a formulation of alginate withappropriate mannuronate and guluronate components into an alginatesolution, and the alginate solution used to form the alginatebioreactor. In another example, an alginate premix of mannuronatealginate subunits and guluronate alginate subunits, an alginate solventsuch as alcohol or water, and one or more therapeutic components andcellular components are combined to form the alginate solution.

In an optional step, one or more viable cell components may be harvestedfrom the host or a donor mammalian body and mixed into the alginatesolution prior to formation of the alginate bioreactor in the mammalianbody, as seen at block 84. The cellular component may be geneticallymanipulated prior to forming the alginate bioreactor. The harvestedcells may be further cultured to increase their numbers or furtherfiltered to obtain the desired quantity, quality and type of cells. Theharvested viable cellular component, such as endogenous endothelialcells, is mixed into the alginate solution prior to injecting thealginate solution. In another example, freeze-dried cells are mixed intothe alginate solution with, for example, an alcohol-based alginatesolvent. The freeze-dried cells are reconstituted after the alginatebioreactor is formed within the mammalian body. In another example,cells from either a host or donor source are preserved with trehaloseand freeze-dried, rendering the cells functional yet in a dehydratedstate. Use of cells in a preserved fashion allows for mixing thealginate solution with the cells in advance or conjointly with themedical procedure. One skilled in the art can identify alternativecell-producing components that can be substituted for endothelial cellsand provide therapeutic products from the alginate matrix.

An alginate linking agent is provided, and the alginate solution and thealginate linking agent are injected into a portion of the mammalian bodywith an alginate injection system. The alginate bioreactor is formed byinjecting an alginate solution and an alginate linking agent into theportion of the mammalian body, and hardening the alginate solution toform the alginate bioreactor. The added alginate linking agentcomprises, for example, divalent calcium, divalent barium, divalentstrontium, divalent magnesium, a divalent cation, or a source of calciumsuch as a calcium salt.

In one example, the alginate linking agent is added to the alginatesolution immediately prior to injecting the alginate solution into theportion of the mammalian body, due to rapid gelling and setting of thealginate matrix. In another example, the alginate linking agent is addedto the alginate solution after injecting the alginate solution into theportion of the mammalian body. In another example, the alginate linkingagent is co-injected into a portion of the mammalian body to form thebioreactor. In another example, the alginate linking agent is depositedin the portion of the mammalian body prior to injecting the alginatesolution. In another example, the alginate linking agent is injectedinto the mammalian body and combined with alginate solution injectedfrom a separate source. In another example, the alginate linking agentis deposited, applied, diffused, or otherwise transferred to the portionof the mammalian body prior to injecting the alginate solution. As thealginate solution is injected, the alginate solution coagulates withinthe portion of the mammalian body to form the alginate bioreactor.

The alginate solution is injected into a portion of the mammalian body,where the alginate solution cross-links, gels, and hardens to form thealginate bioreactor. The alginate bioreactor includes an alginate matrixand one or more therapeutic and cellular components. The amount ofalginate solution injected into the mammalian body is related to thesize, quantity and density of the formed bioreactor.

In one example, the alginate solution is injected into the portion ofthe mammalian body with a syringe having at least one lumen. In anotherexample, alginate solution is injected through a bioreactor formationcatheter into a sidewall of a vessel, heart, or other endoscopicallyaccessible portion of the mammalian body. The bioreactor formationcatheter is positioned, for example, by advancing the distal end of thebioreactor formation catheter over a catheter guidewire to a treatmentsite in the vessel, a medical procedure as is known in the art. Inanother example, the alginate solution is injected into the portion ofthe mammalian body with a high-pressure jet.

Once the alginate bioreactor is formed, one or more therapeutic agentsmay be eluted from therapeutic or cellular components that are dispersedwithin the alginate bioreactor. Exemplary eluted therapeutic agents froman alginate bioreactor having therapeutic or cellular components mayinclude any of the therapeutic agents described above in Section II. Inone example, the eluted therapeutic agent comprises nitric oxide fromentrained endothelial cells to regulate the proliferation of smoothmuscle cells in the mammalian body near the formed alginate bioreactor.In another example, the cellular component is reconstituted in thealginate bioreactor, and the therapeutic agent is released from thereconstituted cellular component.

When a cellular component is employed, an alginate bioreactor is formedby a cellularized alginate solution at a location in the mammalian bodywhere the cellular component is able to produce and elute a therapeuticagent while reconstituting itself for continued production of the agent.The immune barrier of the alginate matrix protects the cellularcomponents while the alginate bioreactor controls the elution of thetherapeutic agent from therapeutic and cellular components within thematrix.

The disclosure set forth above may encompass one or more distinctinventions, with independent utility. Each of these inventions has beendisclosed in its preferred form(s). These preferred forms, including thespecific embodiments thereof as disclosed and illustrated herein, arenot intended to be considered in a limiting sense, because numerousvariations are possible. The subject matter of the inventions includesall novel and nonobvious combinations and subcombinations of the variouselements, features, functions, and/or properties disclosed herein. Thefollowing claims particularly point out certain combinations andsubcombinations regarded as novel and nonobvious. Inventions embodied inother combinations and subcombinations of features, functions, elements,and/or properties may be claimed in applications claiming priority fromthis or a related application. Such claims, whether directed to adifferent invention or to the same invention, and whether broader,narrower, equal, or different in scope to the original claims, also areregarded as included within the subject matter of the inventions of thepresent disclosure.

1. A coated stent, comprising: a stent latticework; and an alginatecoating disposed on the stent latticework. 2-6. (canceled)
 7. The coatedstent of claim 1 further comprising: a therapeutic component dispersedwithin the alginate coating, wherein the therapeutic component acts assource of a therapeutic agent, and wherein the alginate coating controlselution of the therapeutic agent from the alginate coating.
 8. Thecoated stent of claim 7, wherein the therapeutic component is selectedfrom the group consisting of an anti-coagulant, an anti-platelet drug,an anti-thrombotic drug, an anti-proliferant, an inhibitory agent, ananti-stenotic substance, heparin, a heparin peptide, an anti-cancerdrug, an anti-inflammatant, nitroglycerin, L-arginine, an amino acid, anutraceutical, an enzyme, a nitric oxide synthase, a diazeniumdiolate,matrix metalloproteinase, a nitric oxide donor, rapamycin, a rapamycinanalog, paclitaxel, a paclitaxel analog, a coumadin therapy, a lipase,and a combination thereof.
 9. The coated stent of claim 1 furthercomprising: a cellular component dispersed within the alginate coating,wherein the cellular component controllably releases a therapeutic agentwhen the coated stent is deployed within a vessel of a mammalian body.10. (canceled)
 11. The coated stent of claim 9, wherein the releasedtherapeutic agent includes nitric oxide.
 12. (canceled)
 13. A method oftreating a vessel in a mammalian body, the method comprising: providinga stent latticework; coating the stent latticework with an alginatesolution to form a coated stent having an alginate coating disposed onthe stent latticework; positioning the coated stent within the vessel;deploying the coated stent; and eluting a therapeutic agent from thealginate coating. 14-16. (canceled)
 17. The method of claim 13, whereinthe alginate coating includes one of a therapeutic component or acellular component. 18-19. (canceled)
 20. The method of claim 13 furthercomprising: determining a ratio of mannuronate alginate subunits andguluronate alginate subunits to provide a predetermined elutioncharacteristic of the alginate coating; mixing mannuronate alginatesubunits, guluronate alginate subunits, an alginate solvent, and one ofa therapeutic component or a cellular component to form an alginatesolution with the determined ratio of mannuronate alginate subunits andguluronate alginate subunits; adding an alginate linking agent to thealginate solution; and coating the stent latticework with the alginatesolution.
 21. (canceled)
 22. The method of claim 13 further comprising:selecting at least one of a therapeutic component and a cellularcomponent; and mixing the selected at least one component into thealginate solution prior to coating the stent latticework.
 23. The methodof claim 13 further comprising: harvesting a viable cellular componentfrom the mammalian body; and mixing the harvested viable cellularcomponent into the alginate solution prior to coating the stentlatticework. 24-25. (canceled)
 26. An alginate coating for animplantable medical device, the alginate coating comprising: an alginatematrix; and at least one of a therapeutic component and a cellularcomponent dispersed within the alginate matrix.
 27. (canceled)
 28. Analginate implant for treating a vessel in a mammalian body, the alginateimplant comprising: an alginate matrix in contact with an endoluminalwall of the vessel; and a central lumen axially extending through thealginate matrix. 29-38. (canceled)
 39. The alginate implant of claim 28,wherein the implant is configured as at least one of a stent and a capfor vulnerable plaque.
 40. A method of treating a vessel in a mammalianbody, the method comprising: forming an alginate implant within thevessel, the alginate implant in contact with an endoluminal wall of thevessel and having a central lumen axially extending through the alginateimplant; and eluting a therapeutic agent from one of a therapeuticcomponent or a cellular component dispersed within the alginate implant.41-48. (canceled)
 49. The method of claim 40 further comprising:determining a ratio of mannuronate alginate subunits and guluronatealginate subunits to provide a predetermined elution characteristic ofthe alginate implant; combining mannuronate alginate subunits,guluronate alginate subunits, the alginate solvent, and the therapeuticcomponent or the cellular component to form the alginate solution withthe determined ratio of mannuronate alginate subunits and guluronatealginate subunits; adding an alginate linking agent into the alcinatesolution: and injecting the alginate solution into a portion of thevessel with an implant formation catheter. 50-52. (canceled)
 53. Asystem for forming an alginate implant in a mammalian body, the systemcomprising: an implant formation catheter having a catheter body; aformation balloon attached to the catheter body near a distal end of thecatheter body; and an alginate-delivery lumen within the catheter body,wherein an alginate implant is formed from an alginate solution injectedthrough the alginate-delivery lumen into a cavity between the formationballoon and an endoluminal wall of the vessel when the formation balloonis inflated. 54-58. (canceled)
 59. A method of forming an alginateimplant in a vessel of a mammalian body, the method comprising:positioning an implant formation catheter in the vessel, the implantformation catheter having a catheter body; inflating a distal occlusionballoon attached to the catheter body near a distal end of the catheterbody; inflating a proximal occlusion balloon attached to the catheterbody proximal to the distal balloon; inflating a medial formationballoon attached to the catheter body between the distal occlusionballoon and the proximal occlusion balloon; injecting an alginatesolution through an alginate-delivery lumen into a cavity formed betweenthe inflated distal occlusion balloon, the inflated proximal occlusionballoon, the inflated medial formation balloon, and an endoluminal wallof the vessel; and hardening the alginate solution to form the alginateimplant. 60-62. (canceled)
 63. A method of forming an alginate implantin a vessel of a mammalian body, the method comprising: positioning animplant formation catheter at a first location in the vessel, theimplant formation catheter having a catheter body; inflating anangioplasty balloon attached to the catheter body near a distal end ofthe catheter body, the angioplasty balloon having an alginate linkingagent disposed on a surface of the angioplasty balloon; depositing thealginate linking agent on an endoluminal wall of the vessel; deflatingthe angioplasty balloon; repositioning the implant formation catheter ata second location in the vessel, the second location in the vesseldistal to the first location in the vessel; re-inflating the angioplastyballoon; inflating a formation balloon attached to the catheter bodyproximal to the angioplasty balloon; injecting an alginate solutionthrough an alginate-delivery lumen into a cavity formed between theformation balloon and an endoluminal wall of the vessel; and hardeningthe alginate solution to form the alginate implant, wherein the alginatesolution is hardened by the alginate linking agent deposited on theendoluminal wall of the vessel. 64-67. (canceled)
 68. A method offorming an alginate implant in a vessel of a mammalian body, the methodcomprising: inserting an implant formation catheter into the vessel, theimplant formation catheter having at least one formation balloon;injecting an alginate solution into a cavity formed between theformation balloon and an endoluminal wall of the vessel when theformation balloon is inflated; hardening the alginate solution to formthe alginate implant; and withdrawing the implant formation catheterfrom the vessel, wherein the formed alginate implant is in contact withthe endoluminal wall of the vessel and includes a central lumen axiallyextending through the alginate implant.
 69. An alginate bioreactor fortreating a mammalian body, the alginate bioreactor comprising: analginate matrix; and one of a therapeutic component or a cellularcomponent dispersed within the alginate matrix, wherein a therapeuticagent is eluted from the alginate matrix after the alginate bioreactoris formed within the body.
 70. (canceled)
 71. The alginate bioreactor ofclaim 69, wherein the alginate bioreactor is formed in a portion of themammalian body, the portion of the mammalian body selected from thegroup consisting of a heart, a liver, a pancreas, a kidney, an eyeball,a pericardial space, a cerebral spinal space, a periorganic space, anorgan, a vessel, and a tissue. 72-76. (canceled)
 77. The alginatebioreactor of claim 69, wherein the eluted therapeutic agent is selectedfrom the group consisting of vascular endothelial growth factor, abiological anti-inflammatory agent, vitamin C, acetylsalicylic acid, alipid lowering compound, a high-density lipoprotein cholesterol, astreptokinase, a kinase, a thrombolytic agent, an anti-thrombotic agent,a blood-thinning agent, a coumadin material, an anti-cancer agent, anangiogenic agent, an anti-angiogenic agent, an anti-rejection agent, ahormone, a therapeutic component, a cellular component, and acombination thereof.
 78. A method of treating a medical condition in amammalian body, the method comprising: forming an alginate bioreactorwithin a portion of the mammalian body, the alginate bioreactorincluding an alginate matrix; and eluting a therapeutic agent from oneof a therapeutic component or a cellular component dispersed within thealginate bioreactor. 79-97. (canceled)